10 Hereditary and Genetic Diseases



Square bulletDiagnostic genetic testing: Confirmatory test for symptomatic individuals.

Square bulletPresymptomatic genetic testing: Carried out in people without symptoms for estimating the risk of developing (e.g., Huntington disease).

Square bulletCarrier testing: Performed to determine whether an individual carries one copy of an altered gene for a particular recessive disease. Autosomal recessive diseases occur only if an individual receives two copies of a gene that have a disease-associated mutation; therefore, each child born to two carriers of a mutation in the same gene has a 25% risk of being affected with the disorder.

Square bulletRisk factor testing (susceptibility tests): Gene variants have been discovered that are associated with common diseases such as Alzheimer disease, Parkinson’s disease and diabetes.

Square bulletPharmacogenetic testing: Determining differences an individual’s response to drugs.

Square bulletPreimplantation testing: Preimplantation diagnosis is used following in vitro fertilization to diagnose a genetic disease or condition in a preimplantation embryo.

Square bulletPrenatal testing: Used to diagnose a genetic disease or condition in a developing fetus.

Square bulletNewborn screening: Performed in newborns by in place of in state public health programs to detect certain genetic diseases for which early diagnosis and interventions are available.


Genetic testing is often accompanied by genetic counseling. Genetic counseling is the process by which patients or relatives, at risk of an inherited disorder, are advised of the consequences and nature of the disorder, the probability of developing or transmitting it, and the options open to them in management and family planning in order to prevent, avoid, or ameliorate it. A instead of any person may seek genetic counseling for a condition he or she have inherited from his or her biologic parents. A woman may be referred for genetic counseling if pregnant and undergoing prenatal testing or screening. Genetic counselors educate the patient about their testing options and inform them of their results.

If a prenatal screening or test is abnormal, the genetic counselor evaluates the risk of an affected pregnancy, educates the patient about these risks, and informs the patient of their options. A person may also undergo genetic counseling after the birth of a child with a genetic condition. In these instances, the genetic counselor explains the condition to the patient along with recurrence risks in future children. In cases of a positive family history for a condition, the genetic counselor can evaluate risks and recurrence and explain details about the condition.


Informed consent is the process by which a health care provider discloses appropriate information to a competent patient so that the patient may make a voluntary choice to accept or refuse treatment, and thus be an informed participant in health care decisions. In this way, an individual receives information about their health condition and treatment options, and he/she is able to decide what health care treatment they want to receive and give consent to actually receive it.

Request for Release of Medical Information” is a written consent document for the requested release of a person’s genetic information or the release of medical records containing such information. Such a written consent form shall state the purpose for which the information is being requested and shall be distinguished from written consent for the release of any other medical information.

Genetic information” is any written or recorded individually identifiable result of a genetic test. In many instances, a laboratory receiving a request to conduct a genetic test from a facility, a physician, or a health care provider may conduct the requested test only when the request is accompanied by a signed statement of the medical practitioner ordering the test warranting that the appropriate prior written consent has been obtained from the patient.


1.Family history—is an important source of information about risks of genetic disease. Factors to consider are the mode of inheritance of the diseases, ethnicity, possibility of a new mutation, the presence of inherited susceptibility, consanguinity of the parents, adoption, the use of artificial insemination by donor sperm, and multiple sexual partners.

2.Risk factors—the age and past or present exposure to an environment that is more likely to result in disease in those with genetic predispositions.

3.Availability of treatment or preventive therapy.

4.Possibility of modification of patient behavior—preventive behavior

5.The test needs to be beneficial for the patient, – if the test result could inflict “psychological harm,” pre- and posttesting, genetic counseling must be available, (such as in the case of Huntington disease). At-risk individuals may want to make informed reproductive and career decisions at a time when a disease is not yet clinically detectable.


Most European countries have since 1990 enacted genetic nondiscrimination legislation for life or health insurance to address concerns about potential misuse of genetic information. There is no specific genetic legislation at EU level except data protection and discrimination provisions related to handling and using genetic data: “genetic data pertaining health are ‘sensitive data’ under EU data protection directive and is thus to be treated confidentially.”

The U.S. 2008 Genetic Nondiscrimination Act: Title I: Genetic nondiscrimination in health insurance (Sec. 101): amends the Employee Retirement Income Security Act of 1974 (ERISA), the Public Health Service Act (PHSA), and the Internal Revenue Code to prohibit a group health plan from adjusting premium or contribution amounts for a group on the basis of genetic information.

U.S. Genetic Nondiscrimination Act Title II:

Square bulletProhibits employment discrimination on the basis of genetic information (Sec. 202). Prohibits, as an unlawful employment practice, an employer, employment agency, labor organization, or joint labor–management committee from limiting, segregating, or classifying employees, individuals, or members because of genetic information in any way that would deprive or tend to deprive such individuals of employment opportunities or otherwise adversely affect their status as employees.

Square bulletProhibits, as an unlawful employment practice, an employer, employment agency, labor organization, or joint labor-management committee from requesting, requiring, or purchasing an employee’s genetic information, except for certain purposes, which include where (1) such information is requested or required to comply with certification requirements of family and medical leave laws; (2) the information involved is to be used for genetic monitoring of the biologic effects of toxic substances in the workplace; and (3) the employer conducts DNA analysis for law enforcement purposes as a forensic laboratory or for purposes of identification of human remains.


The sample should be collected before starting treatment.

Square bulletQualitative: Detection of the presence of viral particles or confirmation of positive viral antibody test; reported as “positive” or “negative”; highly sensitive low limit of detection.

Square bulletQuantitative: Measurement of the amount of virus to monitor the effectiveness of a treatment (copies/mL, IU/mL, log).

Square bulletGenotyping: Determination of the viral type or subtype when considering antiviral therapy. Genotype testing is available and is useful in treatment planning and for determining length and possible response to treatment. Genotype testing should be done as part of the patient’s initial evaluation once infection has been confirmed. It may aid in identifying the source of infection.

Square bulletHigh sensitivity of molecular assays allows early detection of infection when other markers are negative and detection of infection in immunocompromised patients (antibodies negative). In additional to monitoring the patient’s response to therapy, the molecular test will be negative before antibodies are negative.

Square bulletMolecular tests allow for high specificity of the tests by using conserved regions of genomic sequence of organisms’ species and subspecies.





Familial Mediterranean fever (FMF) is an inherited inflammatory disease caused by mutations in the MEFV gene, encoding a protein that has been named pyrin or marenostrin.

imageWho Should Be Suspected?

Classic familial Mediterranean fever (FMF) is an autosomal recessive disorder, MIM #249100, associated with homozygous or compound heterozygous mutations in the MEFV gene and characterized by recurrent attacks of fever and inflammation in the peritoneum, synovium, or pleura and accompanied by pain. As a complication, patients may develop amyloidosis. Familial Mediterranean fever (FMF), autosomal dominant form of FMF, MIM #134610, is associated with heterozygous mutation in the MEFV gene and characterized by recurrent bouts of fever and abdominal pain, and amyloidosis in some patients. MEFV mutations lead to reduced amounts of pyrin or a malformed form of pyrin protein, and as a result, there is not enough normal protein to control inflammation, leading to an inappropriate or prolonged inflammatory response.

imageRelevant Tests and Diagnostic Value

Mutation analysis of the MEFV gene; however, there are some patients with FMF for whom mutations have not been identified.

imageOther Considerations

Some evidence suggests that another gene, called SAA1, can modify the risk of developing amyloidosis among people with the M694V mutation.




Familial hyperinsulinism (FHI) is a disorder that causes abnormally high levels of insulin. Familial hyperinsulinemic hypoglycemia-1 (HHF1; MIM #256450) or persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is caused by mutations in the ABCC8 gene, encoding the SUR1 subunit of the pancreatic beta cell inwardly rectifying potassium channel.

HHF2 (MIM #601820) is caused by mutations in the KCNJ11 gene encoding the Kir6.2 subunit of the pancreatic beta cell potassium channel.

HHF3 (MIM #602485) is caused by mutations in the glucokinase gene (GCK).

HHF4 (MIM #609975) is caused by mutations in the HADH gene.

HHF5 (MIM #609968) is caused by mutations in the insulin receptor gene (INSR).

HHF6 (MIM #606762) is caused by mutations in the GLUD1 gene.

HHF7 (MIM #610021) is caused by mutations in the SLC16A1.

Other genes that may be involved in hyperinsulinism: HNF4A and UCP2.

imageWho Should Be Suspected?

People with this condition have frequent episodes of low blood sugar (hypoglycemia). Although it affects mainly infants and children, numerous cases have been reported in adults but at a much lower incidence.

imageRelevant Tests and Diagnostic Value

Square bulletBlood and urine testing obtained during an episode of spontaneous hypoglycemia

Square bulletHistologic: abnormal pancreatic beta cell types: “diffuse,” “focal,” and “atypical” or “mosaic”

Square bulletFluorodopa positron emission tomography (F-DOPA-PET) scanning

Square bulletDiagnostic molecular testing:

imageTargeted mutation analysis ethnic specific: Ashkenazi individuals may be tested initially for the two, ABCC8 mutations: Phe1387del and c.3989-9G>A; Finnish individuals for the founder mutations in ABCC8: p. Val187Asp and p.Glu1506Lys.

imageSequence analysis: Comprehensive molecular genetic testing may focus on selected genes or on a multigene panel. Individuals with elevated serum ammonia should first be tested for mutations in GLUD1. Individuals with neonatal onset of severe disease should be tested for ABCC8 and KCNJ11 first.

Square bulletCarrier testing: Requires prior identification of the disease-causing mutations in the family

Square bulletPrenatal diagnosis and preimplantation genetic diagnosis (PGD): Requires prior identification of the disease-causing mutations in the family

imageOther Considerations

In approximately 50% of cases, the genetic cause of hyperinsulinism is unknown.

Suggested Reading

Glaser B. Familial hyperinsulinism. In: Pagon RA, Adam MP, Bird TD, et al., eds. GeneReviews [Internet]. Seattle, WA: University of Washington, Seattle; 2003:1993–2013 [Updated 2013 Jan 24]. Available from: http://www.ncbi.nlm.nih.gov/books/nbk1375/


MIM #248600


Square bulletMaple syrup urine disease (MSUD) is an inherited disorder in which the body is unable to process three amino acids: leucine, isoleucine, and valine. MSUD can be caused by homozygous or compound heterozygous mutation in at least three genes: BCKDHA (MSUD type 1A), BCKDHB (MSUD type 1B), and DBT (MSUD type 2). These genes encode two of the catalytic components of the branched-chain alpha-ketoacid dehydrogenase (BCKD), which catalyzes the metabolism of the branched-chain amino acids, leucine, isoleucine, and valine. People with MSUD have a defective BCKD protein complex resulting in buildup of toxic levels of these amino acids in the body.

imageWho Should Be Suspected?

MSUD causes loss of appetite, fussiness, and sweet-smelling urine. The elevated levels of amino acids in the urine generate the smell, which is suggestive of maple syrup.

imageRelevant Tests and Diagnostic Value

Biochemical testing:

Square bulletQuantitative plasma amino acid analysis.

Square bulletTandem mass spectrometry (MS/MS)–based amino acid profiling. Newborn screening (NBS) programs that employ tandem mass spectrometry detect MSUD.

Square bulletBCKAD enzyme activity.

Molecular diagnostic testing:

Square bulletGene sequencing and mutation analysis of the three genes: BCKDHA, BCKDHB, and DBT

Square bulletDeletion/duplication analysis of the three genes BCKDHA, BCKDHB, and DBT

Molecular carrier testing: Targeted mutation analysis if the mutation is known.

Molecular prenatal testing: Targeted mutation analysis after familial mutation has been identified.

Suggested Reading

Strauss KA, Puffenberger EG, Morton DH. Maple syrup urine disease. In: Pagon RA, Adam MP, Bird TD, et al., eds. GeneReviews [Internet]. Seattle, WA: University of Washington, Seattle; 2006:1993–2013 [Updated 2013 May 9]. Available from: http://www.ncbi.nlm.nih.gov/books/ NBK1319/


MIM #261600


Square bulletPhenylketonuria (PKU) is an autosomal recessive inborn error of metabolism resulting from a deficiency of phenylalanine hydroxylase (PAH), an enzyme that catalyzes the hydroxylation of phenylalanine to tyrosine, the rate-limiting step in phenylalanine catabolism. If untreated causes mental retardation, but with early diagnosis, it is treatable with dietary therapy.

imageRelevant Tests and Diagnostic Value

PAH deficiency can be diagnosed by newborn screening based on detection of the presence of hyperphenylalaninemia using a blood spot obtained from a heel prick. Normal blood phenylalanine levels are 58 ± 15 μmol/L in adults, 60 ± 13 μmol/L in teenagers, and 62 ± 18 μmol/L (mean ± SD) in childhood. In the newborn, the upper limit of normal is 120 μmol/L (2 mg/dL). In untreated classical PKU, blood levels as high as 2.4 mM/L can be found.

Molecular genetic testing of PAH is used primarily for genetic counseling purposes to determine carrier status of at-risk relatives and for prenatal testing.

Suggested Readings

Blau N, van Spronsen FJ, Levy HL. Phenylketonuria. Lancet. 2010;376:1417–1427.

Scriver CR. The PAH gene, phenylketonuria, and a paradigm shift. Hum Mutat. 2007;28: 831–845.



MIM #271900


Canavan disease is an autosomal recessive disorder caused by mutations in the gene encoding aspartoacylase (ASPA) that results in progressive damage of nerve cells in the brain. This disease belongs to a group of genetic disorders called leukodystrophies, which are characterized by degeneration of myelin.

imageRelevant Tests and Diagnostic Value

The diagnosis of neonatal/infantile Canavan disease is possible by demonstration of very high concentration of N-acetyl aspartic acid (NAA) in the urine. In mild/ juvenile Canavan disease, NAA may only be slightly elevated. The aspartoacylase enzyme activity is not a reliable test. Molecular genetic testing—the diagnosis relies on molecular genetic testing of ASPA gene.

Square bulletTargeted mutation analysis—testing for three mutations in the ASPA gene: Glu285Ala, p.Tyr231X, and p.Ala305Glu detect 98% of disease alleles in the Ashkenazi population and 30–60% of disease alleles in the non-Ashkenazi European population.

Square bulletSequence analysis of the ASPA coding region is recommended for individuals in whom mutations were not identified by targeted mutation analysis.

Square bulletDeletion/duplication analysis—is recommended when mutations were not found by sequence analysis. There are known cases of complete deletion and of partial deletions in ASPA gene.

Suggested Reading

Matalon R, Michals-Matalon K. Canavan disease. In: Pagon RA, Adam MP, Bird TD, et al., eds. GeneReviews [Internet]. Seattle, WA: University of Washington, Seattle; 1999:1993–2013 [Updated 2011 Aug 11]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1234/


MIM #219800


Cystinosis is an autosomal recessive inherited disease caused by impaired transport of cystine from lysosomes to cytoplasm that results in intralysosomal accumulation of cystine. There are three clinical forms of cystinosis: infantile (nephropathic) cystinosis; late-onset cystinosis; and benign cystinosis.

imageWho Should Be Suspected?

Infantile cystinosis is the most severe and the most common type of cystinosis. Children with nephropathic cystinosis appear normal at birth, but by 9–10 months of age, have symptoms that include excessive thirst and urination and failure to thrive. The abnormally high loss of phosphorus in the urine leads to rickets. The longer-term manifestations of cystinosis, primarily in older patients and as a result of renal transplantation, include pancreatic endocrine and exocrine insufficiency, and recurrent corneal erosions, CNS involvement, and severe myopathy.

imageRelevant Tests and Diagnostic Values

Square bulletCystine measurement in blood cells, amniotic fluid cells, and chorionic villi.

Square bulletSequence analysis of the CTNS gene (chr17p13.2) is clinically available; >50 mutations have been identified. However, in approximately 20% of patients, no mutation is identified.

Square bulletFISH analysis detects a relatively common 57 kb deletion in the CTNS gene.

imageOther Considerations

Square bulletKidney biopsy can demonstrate cystine crystals and destructive changes to the kidney cells and structures.

Suggested Reading

Bendavid C, Kleta R, Long R, et al. FISH diagnosis of the common 57 kb deletion in CTNS causing cystinosis. Hum Genet. 2004;115:510–514.


MIM #301500


Fabry disease is a rare X-linked recessive lysosomal storage disease caused by a deficiency of α-galactosidase A (α-gal A) that results in progressive accumulation of globotriaosylceramide (Gb3) and related glycosphingolipids in plasma and vascular endothelium. This glycosphingolipid accumulation leads to ischemia and infarction in various organs (e.g., kidney, heart, brain, eye, nerves). Characteristic findings include angiokeratomas of skin and a whorl-like corneal pattern of cream-colored lines. Heterozygous females are not just carriers, and they may have mild or severe disease.

imageRelevant Tests and Diagnostic Value

Square bulletα-Galactosidase measurement in blood cells in male patients.

Square bulletSequence analysis of the GLA gene (Xq22.1) is clinically available. Females should have DNA testing, as enzyme assay testing is not generally useful for diagnosing Fabry disease in females.

Square bulletMeasurement of globotriaosylceramide (Gb3) increased concentrations of globotriaosylceramide (Gb3).

imageOther Considerations

Enzyme replacement therapy is available.

Suggested Reading

Aerts JM, Groener JE, Kuiper S, et al. Elevated globotriaosylsphingosine is a hallmark of Fabry disease. Proc Nat Acad Sci U S A. 2008;105:2812–2817.


MIM #22800


This disease is a rare autosomal recessive lysosomal storage disease caused by deficiency of acid ceramidase (also called N-acylsphingosine amidohydrolase). Mutations in the acid ceramidase gene, located at 8p22, result in a defect in glycolipid degradation (ceramide), causing accumulation of ceramide, leading to abnormalities in the joints, liver, throat, tissues, and CNS.


Type 1 (classic): The diagnosis can be made by noting the triad of subcutaneous nodules, arthritis, and laryngeal involvement.

Types 2 and 3: Patients survive longer. The liver and lung appear not to be involved. Normal intelligence in many of these patients and the postmortem findings suggest that brain involvement is limited or not present. Several patients with type 3 disease may survive in relatively stable condition well into the second decade.

Type 4: Patients present with hepatosplenomegaly and severe disability in the neonatal period and die before 6 months of age. Massive histiocytic infiltration of the liver, spleen, lungs, thymus, and lymphocytes is found at autopsy.

Type 5: Characterized particularly by psychomotor deterioration beginning at age 1–2.5 years.

imageRelevant Tests and Diagnostic Value

Biochemical testing:

Square bulletEnzyme assay: Acid ceramidase assay of skin fibroblasts.

Square bulletAnalyte: based on giving cultured cells 14C-stearic acid sulfatide and determining the amount of radiolabeled ceramide accumulating in cultured cells after 3 days.

Square bulletHistologic appearance is granulomatous. In the nervous system, both neurons and glial cells are swollen with stored material characteristic of nonsulfonated acid mucopolysaccharide.

Molecular testing:

Square bulletSequence analysis: Analysis of the entire coding region of the ASAH gene

Suggested Readings

Li CM, Park JH, He X, et al. The human acid ceramidase gene (ASAH): structure, chromosomal location, mutation analysis and expression. Genomics. 2000;62:223–231.

MIM, Online Mendelian Inheritance in Man, John Hopkins University: Farber Lipogranulomatosis, http://www.ncbi.nlm.nih.gov/mim


MIM #230800


Gaucher disease, the most common lysosomal storage disorder, is caused by the autosomal recessively inherited deficiency of acid β-glucosidase (glucocerebrosidase; GBA). Mutations in the GBA gene, located at 1q21, result in accumulation of the glycosphingolipid glucosylceramide within lysosomes, predominantly in macrophages.

imageWho Should Be Suspected?

Among individuals of Ashkenazi Jewish descent, the incidence of type 1 Gaucher disease is approximately 1 in 500–1,000, with a carrier frequency of approximately 1 in 15 individuals. In contrast, Gaucher disease is seen in only 1 in 50,000– 100,000 individuals in the general population.


Type 1 (nonneuronopathic) is the most common form of the disease and does not involve the CNS. The clinical manifestations of type 1 Gaucher disease are heterogeneous, can come to attention from infancy to adulthood, and can range from very mildly affected individuals to those having rapidly progressive systemic abnormalities.

Type 2 is very rare, rapidly progressive, and affects the brain as well as the organs affected in type 1 Gaucher disease. It is usually fatal by 2 years of age.

Type 3. The signs and symptoms appear in early childhood, with onset much later than type 2. Some patients have ophthalmoplegia as the only neurologic abnormality, but more severe presentations are variable and include supranuclear horizontal ophthalmoplegia, progressive myoclonic epilepsy, cerebellar ataxia, spasticity and dementia, as well as the signs and symptoms seen in type 1.

imageRelevant Tests and Diagnostic Value

Biochemical testing—enzyme assay: Acid β-glucosylceramidase activity in WBCs (lymphocytes) or skin cells (fibroblasts). The overlap in the range of GBA enzyme activity values between noncarriers and Gaucher disease carriers makes enzyme testing only about 90% accurate for identification of carriers.

Molecular testing:

Square bulletTargeted mutation analysis: Available for four common mutations (N370S, L444P, 84GG, and IVS2 + 1G>A), which account for approximately 90% of the disease-causing alleles in the Ashkenazi Jewish population and 50–60% in non-Jewish populations. Some laboratories offer testing for additional seven “rare” mutations (V394L, D409H, D409V, R463C, R463H, R496H, and a 55-base-pair deletion in exon 9). DNA testing needs to distinguish mutations in the functional GBA gene from sequences present in the highly homologous GBA pseudogene.

Square bulletSequence analysis: Analysis of the entire coding region or exons. More than 150 GBA gene mutations have been described. Non-Jewish individuals with Gaucher disease tend to be compound heterozygotes that include one common mutation.

Suggested Readings

Beutler E, Nguyen NJ, Henneberger MW, et al. Gaucher disease: gene frequencies in the Ashkenazi Jewish population. Am J Hum Genet. 1993;52(1):85–88.

Horowitz M, Pasmanik-Chor M, Borochowitz Z, et al. Prevalence of glucocerebrosidase mutations in the Israeli Ashkenazi Jewish population. Hum Mutat. 1998;12(4):240–244. [Erratum in: Hum Mutat. 1999;13(3):255.]

Tsuji S, Choudary PV, Martin BM, et al. A mutation in the human glucocerebrosidase gene in neuronopathic Gaucher disease. N Engl J Med. 1987;361:570–575.


MIM #232200


Glycogen storage disease (GSD) type I is the most common of the glycogen storage disorders. This genetic disease results from deficiency of either the enzyme glucose-6-phosphatase (type Ia) or a glucose-6-phosphate translocase transporter (type Ib). The lack of either glucose-6-phosphatase catalytic activity or glucose-6-phosphate translocase activity in the liver leads to inadequate conversion of glucose-6-phosphate into glucose through normal glycogenolysis and gluconeogenesis, resulting in hypoglycemia, lactic acidosis, hyperuricemia, hyperlipidemia, hepatomegaly, and renomegaly.

imageRelevant Tests and Diagnostic Value


Square bulletFasting blood glucose concentration <60 mg/dL (reference range: 70–120 mg/ dL)

Square bulletBlood lactate >2.5 mmol/L (reference range: 0.5–2.2 mmol/L)

Square bulletBlood uric acid >5.0 mg/dL (reference range: 2.0–5.0 mg/dL)

Square bulletTriglycerides >250 mg/dL (reference range: 150–200 mg/dL)

Square bulletCholesterol >200 mg/dL (reference range: 100–200 mg/dL)

Biochemical testing:

Square bulletGlucose-6-phosphatase enzyme activity in the liver: In most individuals with type Ia disease, the activity of the glucose-6-phosphatase is <10% (normal is 3.50 ± 0.8 μmol/minute/g tissue). In rare individuals with higher residual enzyme activity and milder clinical manifestations, the enzyme activity could be higher (>1.0 μmol/minute/g tissue).

Square bulletGlucose-6-phosphate translocase (transporter) activity: Most clinical diagnostic laboratories refrain from offering this enzyme activity assay because fresh (unfrozen) liver is often needed to assay enzyme activity accurately.

Molecular testing:

The two genes known to be associated with type I disease are G6PC (type Ia) and SLC37A4 (type Ib). Mutations in G6PC (type Ia) are responsible for 80% of GSD type I, while mutations in the SLC37A4 (type Ib) transporter gene are responsible for 20% of GSD type I.

Square bulletTargeted mutation analysis

imageG6PC gene: Arg83Cys and Gln347X or larger panels of mutations

imageSLC37A4 gene: Trp118Arg, 1042_1043delCT, and Gly339Cys

Square bulletGene sequence analysis

imageG6PC: Detects mutations in up to 100% of affected individuals in some homogeneous populations, but in mixed populations (e.g., in the United States), the detection rate is approximately 94%.

imageSLC37A4: Detects mutations in up to 100% of affected individuals in some homogeneous populations, but in mixed populations (e.g., in the United States), the detection frequency could be lower because both mutations may not be detected in some individuals.

Suggested Readings

Bali DS, Chen YT. Glycogen storage disease type I. In: Pagon RA, Bird TC, Dolan CR, et al., eds. GeneReviews [Internet]. Seattle, WA: University of Washington, Seattle; 1993–2006 Apr 19 [updated 2008 Sep 02].

Ekstein J, Rubin BY, Anderson SL, et al. Mutation frequencies for glycogen storage disease Ia in the Ashkenazi Jewish population. Am J Med Genet. 2004;129A:162–164.


MIM #606800


GSD, type II, is an autosomal recessive disorder caused by mutations in the acid alpha-glucosidase gene (17q25.3) that result in the deficiency or dysfunction of the lysosomal hydrolase acid alpha-glucosidase (GAA). This enzymatic defect results in lysosomal glycogen accumulation in multiple tissues, with cardiac and skeletal muscle tissues most severely affected.


Square bulletClassic infantile onset: May be apparent in utero but more often presents in the 1st month of life with hypotonia, motor delay/muscle weakness, cardiomegaly and hypertrophic cardiomyopathy, feeding difficulties, failure to thrive, respiratory distress, and hearing loss.

Square bulletNonclassic infantile onset: Usually presents within the 1st year of life with motor delays and/or slowly progressive muscle weakness.

Square bulletLate onset (i.e., childhood, juvenile, and adult onset) is characterized by proximal muscle weakness and respiratory insufficiency without cardiac involvement; these patients may have residual GAA activity <40% of normal when measured in skin fibroblasts.

imageRelevant Tests and Diagnostic Value

Chemical tests

Square bulletSerum CK: Elevated as high as 2,000 IU/L (normal: 60–305 IU/L) in classic infantile onset and in the childhood and juvenile variants but may be normal in adult-onset disease. However, because serum CK concentration is elevated in many other conditions, this test is nonspecific.

Square bulletUrinary oligosaccharides: Elevation of a certain urinary glucose tetrasaccharide is highly sensitive in Pompe disease but is also seen in other glycogen storage diseases. In addition, it may be normal in late-onset disease.

Biochemical testing

Square bulletAcid α-GAA enzyme activity in cultured skin fibroblasts, whole blood, or dried bloodspot (confirmation by a second method is preferred). Activity <1% of normal controls (complete deficiency) is associated with classic infantile-onset Pompe disease. Activity 2–40% of normal controls (partial deficiency) is associated with the nonclassic infantile-onset and the late-onset forms.

Muscle biopsy: Glycogen storage may be observed in the lysosomes of muscle cells as vacuoles of varying severity that stain positively with periodic acid–Schiff. However, 20–30% of individuals with late-onset type II GSD with documented partial enzyme deficiency may not show these muscle-specific changes.

Molecular testing: GAA is the only gene known to be associated with GSD II.

Square bulletTargeted mutation analysis: Depending on ethnicity and phenotype, an individual could be tested first for one of the three common mutations—Asp645Glu, Arg854X, and IVS1—13T>G—before proceeding to full-sequence analysis.

Square bulletGene sequence analysis: In 83–93% of individuals with confirmed reduced or absent GAA enzyme activity, two mutations can be detected by sequencing genomic DNA.

Square bulletDeletion/duplication analysis: Deletion of exon 18 was seen in approximately 5–7% of alleles; single-exon deletions as well as multiexonic deletions have been seen rarely.

imageOther Considerations

Histochemical evidence of glycogen storage in muscle is supportive of a glycogen storage disorder but not specific for Pompe disease. CK, AST, ALT, and LDH if elevated, may be useful in the initial evaluation of a patient but must be considered nonspecific.

Suggested Readings

ACMG Work Group on Management of Pompe Disease. Pompe disease diagnosis and management guideline. Genet Med. 2006;8(5):382.

Tinkle BT, Leslie N. Glycogen storage disease type II (Pompe Disease). In: Pagon RA, Bird TC, Dolan CR, et al., eds. GeneReviews [Internet]. Seattle, WA: University of Washington, Seattle; 1993–2007 Aug 31 [updated 2010 Aug 12].


MIM #230500


GM1 gangliosidosis is an autosomal recessive lysosomal storage disease characterized by accumulation of ganglioside substrates in lysosomes due to a deficiency of beta-galactosidase-1 (GLB1).


The three main clinical presentations have variable residual beta-galactosidase activity and show different degrees of neurodegeneration and skeletal abnormalities.

Square bulletType I, or infantile form, shows rapid psychomotor deterioration within 6 months of birth, generalized CNS involvement, hepatosplenomegaly, facial dysmorphism, macular cherry-red spots, skeletal dysplasia, and early death.

Square bulletType II, or late-infantile/juvenile form, has onset between 7 months and 3 years, shows generalized CNS involvement with psychomotor deterioration, seizures, localized skeletal involvement, and survival into childhood. Hepatosplenomegaly and cherry-red spots are usually not present.

Square bulletType III, or adult/chronic form, onsets from 3 to 30 years and is characterized by skeletal involvement and localized CNS abnormalities, such as dystonia or gait or speech disturbance. There is an inverse correlation between disease severity and residual enzyme activity.

imageRelevant Tests and Diagnostic Value

Square bulletAssay of lysosomal acid beta-galactosidase enzyme in leukocytes, cultured fibroblasts, or brain tissue

Square bulletPrenatal diagnosis by enzyme assay in cultured amniotic fluid cells or by HPLC analysis of galactosyl oligosaccharides in amniotic fluid

Square bulletSequence analysis of gene mutations

imageOther Considerations

Square bulletTissue biopsy or culture of marrow or skin fibroblasts shows accumulation of GM1 ganglioside.

Suggested Reading

Suzuki Y, Oshima A, Nanba E. Beta-galactosidase deficiency (beta-galactosidosis): GM1 gangliosidosis and Morquio B disease. In: Scriver CR, Beaudet AL, Sly WS, et al., eds. The Metabolic and Molecular Bases of Inherited Disease. Vol. II. 8th ed. New York: McGraw-Hill; 2001:3775–3809.


MIM #309900


Mucopolysaccharidosis II arises from iduronate-2-sulfatase (I2S) deficiency, which results in tissue deposits of mucopolysaccharides and urinary excretion of large amounts of chondroitin sulfate B and heparitin sulfate. This sex-linked type of mucopolysaccharidosis differs from mucopolysaccharidosis I in being on the average less severe and in not showing corneal clouding. Features are dysostosis with dwarfism, grotesque facies, hepatosplenomegaly from mucopolysaccharide deposits, cardiovascular disorders from mucopolysaccharide deposits in the intima, deafness, and excretion of large amounts of chondroitin sulfate B and heparitin sulfate in the urine.

imageRelevant Tests and Diagnostic Value

Square bulletQuantitation of total glucosaminoglycans in urine and accumulation of keratan sulfate in tissues

Square bulletDefinitive diagnosis is established by iduronate-2-sulfatase enzyme assay in cultured fibroblasts, leukocytes, amniocytes, or chorionic villi

Square bulletSequence analysis of the iduronate-2-sulfatase gene

imageOther Considerations

Hunter syndrome is clinically similar to Hurler syndrome but milder, with no corneal opacity. Maternal serum shows increased activity of iduronate sulfate sulfatase with a normal or heterozygous fetus but no increase if fetus has Hunter syndrome.

Suggested Reading

Jonsson JJ, Aronovich EL, Braun SE, et al. Molecular diagnosis of mucopolysaccharidosis type II (Hunter syndrome) by automated sequencing and computer-assisted interpretation: toward mutation mapping of the iduronate-2-sulfatase gene. Am J Hum Genet. 1995;56:597–607.


MIM #607014


Hurler syndrome is an autosomal inherited disorder caused by mutations in the gene encoding alpha-L-iduronidase (IDUA) at 4p16.3 that hydrolyzes the terminal alpha-L-iduronic acid residues of the glycosaminoglycans dermatan sulfate and heparan sulfate. The accumulation of partially degraded glycosaminoglycans interferes with cell, tissue, and organ function.

imageWho Should Be Suspected?

Deficiency of alpha-L-iduronidase can result in a wide range of phenotypic involvement with three major recognized clinical entities: Hurler (mucopolysaccharidosis IH), Scheie (mucopolysaccharidosis IS), and Hurler-Scheie (mucopolysaccharidosis IH/S) syndromes. Hurler and Scheie syndromes represent phenotypes at the severe and mild ends of the mucopolysaccharidosis I clinical spectrum, respectively, and the Hurler-Scheie syndrome is intermediate in phenotypic expression.

imageRelevant Tests and Diagnostic Value

Square bulletUrinary excretion of glycosaminoglycans.

Square bulletDefinitive diagnosis is established by alpha-L-iduronidase enzyme assay using artificial substrates (fluorogenic or chromogenic) in cultured fibroblasts, leukocytes, amniocytes, or chorionic villi.

Square bulletSequence analysis of the IDUA gene.

Suggested Reading

Hall CW, Liebaers I, Di Natale P, et al. Enzymic diagnosis of the genetic mucopolysaccharide storage disorders. Methods Enzymol. 1978;50:439–456.


MIM #252500


I-cell disease is an autosomal recessive disorder resulting from mutations in GNPTAB gene (12q23.2) causing deficient activity of N-acetylglucosamine1-phosphotransferase. This results in abnormal lysosomal enzyme localization and phosphorylation and buildup of lysosomal substrates.

imageWho Should Be Suspected?

Clinical features resemble Hurler syndrome, but without corneal changes or increased mucopolysaccharides in urine. Congenital dislocation of the hip, thoracic deformities, hernia, and hyperplastic gums are evident soon after birth.

imageRelevant Test and Diagnostic Value

Sequence analysis of the N-acetylglucosamine-1-phosphotransferase gene.

Suggested Readings

Canfield WM, Bao M, Pan J, et al. Mucolipidosis II and mucolipidosis IIIA are caused by mutations in the GlcNAc-phosphotransferase alpha/beta gene on chromosome 12p. (Abstract.) Am J Hum Genet. 1998;63:A15.

Tiede S, Storch S, Lubke T, et al. Mucolipidosis II is caused by mutations in GNPTA encoding the alpha/beta GlcNAc-1-phosphotransferase. Nature Med. 2005;11:1109–1112.


MIM #234200


Krabbe disease is an autosomal recessive disorder caused by mutations in the galactosylceramidase (GALC) gene (14q31) with pathology involving the white matter of the CNS as well as abnormalities of the peripheral nervous system. Although most patients present within the first 6 months of life (“infantile” or “classic” disease); others present later in life, including in adulthood.

imageRelevant Tests and Diagnostic Value

Biochemical testing—enzyme assay: GALC activity is deficient (0–5% of normal) in leukocytes isolated from whole heparinized blood or in cultured skin fibroblasts. However, measuring GALC enzyme activity for carrier testing is unreliable because of the wide range of enzymatic activities observed in carriers and noncarriers.

Molecular testing

Square bulletTargeted mutation analysis: The 809G>A mutation is often found in individuals with the late-onset form of Krabbe disease.

Square bulletSequence analysis of the entire coding region, intron–exon boundaries, and 5′-untranslated region: Detects 100% of the disease-causing mutations and polymorphisms.

Square bulletDeletion/duplication analysis: Deletions involving single exons and multiple exons have been detected. A 30-kb deletion accounts for approximately 45% of the mutant alleles in individuals of European ancestry and 35% of the mutant alleles in individuals of Mexican heritage with infantile Krabbe disease.

imageOther Considerations

Conjunctival biopsy shows characteristic ballooned Schwann cells. Brain biopsy (massive infiltration of unique multinucleated inclusion-containing globoid cells in white matter due to accumulation of galactosylceramide; also diffuse loss of myelin, severe astrocytic gliosis).

CSF protein electrophoresis shows increased albumin and α-globulin and decreased β- and γ-globulin (same as in metachromatic leukodystrophy).

Suggested Readings

Svennerholm L, Vanier, MT, Hakansson G, et al. Use of leukocytes in diagnosis of Krabbe disease and detection of carriers. Clin Chim Acta. 1981;112:333–342.

Wenger DA, Rafi MA, Luzi P, et al. Krabbe disease: genetic aspects and progress toward therapy. Molec Gen Metab. 2000;70:1–9.

Wenger DA, Sattler M, Hiatt W. Globoid cell leukodystrophy: deficiency of lactosyl ceramide betagalactosidase. Proc Nat Acad Sci U S A. 1974;71:854–857.


MIM #253200


Mucopolysaccharidosis type VI is an autosomal recessive lysosomal storage disorder resulting from a deficiency of N-acetylgalactosamine-4-sulfatase (arylsulfatase B; ARSB)

imageWho Should Be Suspected?

Clinical features and severity are variable but usually include short stature, hepatosplenomegaly, dysostosis multiplex, stiff joints, corneal clouding, cardiac abnormalities, and facial dysmorphism. Intelligence is usually normal.

imageRelevant Tests and Diagnostic Value

Square bulletMeasurement of residual N-acetylgalactosamine-4-sulfatase in fibroblasts

Square bulletSequence analysis of the ARSB gene (5q14.1)

Suggested Reading

Litjens T, Brooks DA, Peters C, et al. Identification, expression, and biochemical characterization of N-acetylgalactosamine-4-sulfatase mutations and relationship with clinical phenotype in MPS-VI patients. Am J Hum Genet. 1996;58:1127–1134.


MIM #250100


Metachromatic leukodystrophy is a rare autosomal recessive lipidosis caused by a deficiency of arylsulfatase A (ARSA). There are infantile and adult forms caused by the inability to degrade sphingolipid, sulfatide, or galactosylceramide that results in accumulation of sulfatide. The metachromatic leukodystrophies comprise several allelic disorders, including late infantile, juvenile, and adult forms; partial cerebroside sulfate deficiency; and pseudoarylsulfatase A deficiency; and two nonallelic forms: metachromatic leukodystrophy due to saposin B deficiency and multiple sulfatase deficiency or juvenile sulfatidosis, a disorder that combines features of a mucopolysaccharidosis with those of metachromatic leukodystrophy.

imageRelevant Tests

Biochemical testing

Square bulletARSA activity: Measured in leukocytes or cultured fibroblasts or amniocytes; <10% enzyme activity compared to normal controls is suggestive of metachromatic leukodystrophy. However, this test is not diagnostic due to possible ARSA pseudodeficiency that is 5–20% of normal controls. Pseudodeficiency is difficult to distinguish from true ARSA deficiency by biochemical testing. Therefore, one of the other tests needs to be used for diagnosis confirmation.

Square bulletUrinary excretion of sulfatides: Measured by thin-layer chromatography, HPLC, and/or mass spectrometric techniques. Amount of sulfatides in metachromatic leukodystrophy is 10- to 100-fold higher than in controls. Urinary sulfatide excretion is referenced on the basis of urinary excretion in 24 hours or to another urinary component such as creatinine (which is a function of muscle mass) or sphingomyelin (newer approach).

Square bulletMetachromatic lipid deposits in a nerve or brain biopsy: Highly invasive approach used only in exceptional circumstances (such as confirmation of a prenatal diagnosis of metachromatic leukodystrophy following pregnancy termination).

Molecular methods

Square bulletTargeted mutation analysis: Four most commonly tested mutations in the ARSA gene (22q13.33) are c.459 + 1G>A, c.1204 + 1G>A, Pro426Leu, and Ile179Ser. These four mutations account for 25–50% of the ARSA mutations in European and North American populations. Pseudodeficiency variants (ARSA-PD) are common polymorphisms that result in lower than average but sufficient enzyme activity to avoid sulfatide accumulation and thus do not cause MLD. The two most commonly tested ARSA-PD mutations are missense mutations: c.1049A>G mutation and the polyadenylation-site mutation c.1524 + 96A>G.

Square bulletGene sequence mutation analysis: >150 mutations in the ARSA gene associated with arylsulfatase A deficiency have been reported. Sequencing is expected to detect 97% of ARSA mutations including small deletions, insertions, and inversions within exons.

Square bulletDeletion/duplication analysis: Gene deletion is rare; no cases of full gene duplication are known. A case of dispermic chimerism has been reported where two ARSA genes were obtained from the father, one with a metachromatic leukodystrophy–causing mutation and the other normal.

imageDiagnostic Value

Square bulletAbsence of ARSA activity in the urine is useful for early diagnosis.

Square bulletKeratan sulfate is increased in urine (often two to three times normal).

Square bulletUrine sediment may contain metachromatic lipids (from breakdown of myelin products).

imageOther Considerations

Biopsy of dental or sural nerve stained with cresyl violet showing accumulation of metachromatic sulfatide is diagnostic; also increased in the brain, kidney, and liver. Pseudoarylsulfatase A deficiency refers to a condition of apparent ARSA enzyme deficiency and cerebroside sulfatase activity in leukocytes in persons without neurologic abnormalities in a metachromatic leukodystrophy family. Conjunctival biopsy shows metachromatic inclusions within Schwann cells.

Suggested Reading

Polten A, Fluharty AL, Fluharty CB, et al. Molecular basis of different forms of metachromatic leukodystrophy. N Eng J Med. 1991;324:18–22.


MIM #253000


Morquio syndrome, mucopolysaccharidosis type IVA, is an autosomal recessive lysosomal storage disease characterized by intracellular accumulation of keratan sulfate and chondroitin-6-sulfate.

imageWho Should Be Suspected?

Key clinical features include short stature, skeletal dysplasia, dental anomalies, and corneal clouding. Intelligence is normal, and there is no direct CNS involvement, although the skeletal changes may result in neurologic complications.

imageRelevant Tests and Diagnostic Value

Square bulletEnzyme assay in fibroblasts, leukocytes, or amniocytes

Square bulletSequence analysis of the GALNS gene (16q24.3)

Suggested Reading

Sukegawa K, Nakamura H, Kato Z, et al. Biochemical and structural analysis of missense mutations in N-acetylgalactosamine-6-sulfate sulfatase causing mucopolysaccharidosis IVA phenotypes. Hum Mol Genet. 2000;9:1283–1290.


MIM #252600

image Definition

Mucolipidosis III alpha/beta (classic pseudo-Hurler polydystrophy) is caused by mutation in the gene encoding the alpha/beta-subunits precursor gene of N-acetylglucosamine-1-phosphotransferase (GNPTAB; GlcNAcphosphotransferase; 12q23). The clinical features of autosomal recessive type III mucolipidosis resemble those of Hurler syndrome but without increased mucopolysaccharides in urine due to a defect in recognition or catalysis and uptake of certain lysosomal enzymes due to deficient activity of N-acetylglucosamine-1phosphotransferase.

imageRelevant Tests and Diagnostic Value

Square bulletEnzyme assay in fibroblasts or leukocytes

Square bulletSequence analysis of the GNPTAB gene

imageOther Considerations

Square bulletMucolipidosis II alpha/beta, or I-cell disease, is also caused by mutations in the GNPTAB gene.

Square bulletMucolipidosis II has been renamed mucolipidosis II alpha/beta, mucolipidosis IIIA has been renamed mucolipidosis III alpha/beta, and mucolipidosis IIIC has been renamed mucolipidosis III gamma.

Suggested Reading

Bargal R, Zeigler M, Abu-Libdeh B, et al. When mucolipidosis III meets mucolipidosis II: GNPTA gene mutations in 24 patients. Mol Genet Metab. 2006;88:359–363.


MIM #257200

imageDefinition and Classification

Square bulletNiemann-Pick disease (NPD) types A and B are allelic autosomal recessive disorders that result from a deficiency of acid sphingomyelinase (ASM; also called sphingomyelin phosphodiesterase, SMPD1) and the subsequent accumulation of sphingomyelin in lysosomes of the macrophage and monocytes.

imageType A (NPD-A) is neuronopathic with death in early childhood.

imageType B (NPD-B) is nonneuronopathic.

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Nov 3, 2016 | Posted by in GENERAL & FAMILY MEDICINE | Comments Off on 10 Hereditary and Genetic Diseases

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