Hereditary and Genetic Diseases

Hereditary and Genetic Diseases

Marzena M. Galdzicka

Patricia Minehart Miron

Edward I. Ginns


Genetic disorders are conditions caused by absent or defective genes or by chromosomal aberrations. Genetic disorders can be tested at the level of DNA, RNA, or protein. A genetic test is the analysis of human DNA, RNA, mitochondrial DNA, chromosomes, proteins, or certain metabolites in order to detect alterations that may be inherited or acquired. This can be accomplished by directly examining the DNA or RNA that makes up a gene (direct testing); looking at markers coinherited with a disease-causing gene (linkage testing), enzyme activity, or metabolites (biochemical testing); or examining the chromosomes (cytogenetic testing) ( The results of a genetic test
can confirm or rule out a suspected genetic condition, determine an individual’s risk of developing disorders, identify carriers, or assess gene variants influencing an individual’s rate of drug metabolism. Hundreds of genetic tests are currently in use and more are being developed. Genetic testing may be undertaken as part of the process of diagnosing, treating, or counseling patients.



  • Diagnostic genetic testing: Confirmatory test for symptomatic individuals.

  • Presymptomatic genetic testing: Carried out in individuals without symptoms for estimating the risk of developing illness (e.g., Huntington disease [HD]).

  • Carrier 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.

  • Risk factor testing (susceptibility tests): Gene variants have been discovered that are associated with common diseases such as Alzheimer disease (AD), Parkinson disease (PD), and diabetes.

  • Pharmacogenetic testing: Determining an individual’s response to drugs.

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

  • Prenatal testing: Used to diagnose a genetic disease or condition in a developing fetus.

  • Newborn screening: Performed on newborns to detect certain genetic diseases for which early diagnosis and management 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. An individual may seek genetic counseling for a condition they have inherited from their biologic parents. A woman may be referred for genetic counseling if pregnant and undergoing prenatal testing or screening. Genetic counselors can 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 they are able to decide and give consent on what health care treatment they want to receive.

Request for release of medical information is a written consent document for the release of a person’s medical information and indicates the purpose for which the information is being requested.

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 ordering medical practitioner attests that written informed consent has been obtained from the patient.


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

  • 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.

  • Availability of treatment or preventive therapy.

  • Possibility of modification of patient behavior—preventive behavior.

  • 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 HD). In this way, at-risk individuals can 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 European Union (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:

  • Prohibits 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

  • Prohibits, 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




□ Who Should Be Suspected?

Classic 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. 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.

□ Relevant Tests and Diagnostic Value

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

□ Other Considerations

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



□ Who Should Be Suspected?

Individuals 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.

□ Relevant Tests and Diagnostic Value

  • Blood and urine testing obtained during an episode of spontaneous hypoglycemia

  • Histologic: abnormal pancreatic beta-cell types: “diffuse,” “focal,” and “atypical” or “mosaic”

  • Fluorodopa positron emission tomography (F-DOPA-PET) scanning

  • Diagnostic molecular testing:

    • ▼ Targeted 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.

    • ▼ Sequence 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.

  • Carrier testing: Requires prior identification of the disease-causing mutations in the family

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

□ Other 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. GeneReviewsTM [Internet]. Seattle, WA: University of Washington, Seattle; 2003:1993-2013 [Updated 2013 Jan 24]. Available from:


MIM #300322

□ Who Should Be Suspected?

Affected males manifest with neurologic dysfunction, cognitive and behavioral disturbances (choreoathetosis, mental retardation, and tendency to self-mutilation), and uric acid overproduction. Clinical manifestations are due to secondary gout (tophi after 10 years, crystalluria, hematuria, urinary calculi, UTI, gouty arthritis, response to colchicine). Patients die of renal failure by age 10 years unless treated. Orange crystals or sand is seen in infants’ diapers.

□ Relevant Tests and Diagnostic Value

  • A urinary urate-to-creatinine ratio >2.0 is characteristic for affected male patients who are younger than 10 years of age but is not considered diagnostic. Neither hyperuricuria nor hyperuricemia (serum uric acid >8 mg/dL; 600-1,000 mg/24 hours in patients weighing ≥15 kg) is specific for diagnosis.

  • Hypoxanthine-guanine phosphoribosyltransferase (HPRT) enzyme activity in male patients <1.5% of normal in blood cells, cultured fibroblasts, amniocytes, or lymphoblasts is diagnostic. The assay is possible on erythrocytes in anticoagulant or on dried blood spots on filter paper. Enzyme assay is not helpful in female patients.

  • Sequence analysis of the HPRT1 gene is available. More than 200 mutations (primarily missense and nonsense mutations and small deletions/insertions) have been identified.

□ Other Considerations

  • Variants with partial deficiency of HGPRT show 0-50% of normal activity in RBC hemolysates and >1.2% in fibroblasts; accumulate purines but no orange sand in diapers or abnormality of CNS or behavior.

  • Probenecid and other uricosuric drugs designed to reduce the serum concentration of uric acid are contraindicated because they augment the delivery of uric acid into the urinary system and raise the risk of acute anuria from deposition of uric acid crystals in the renal collecting system.

Suggested Readings

Jinnah HA, Harris JC, Nyhan WL, et al. The spectrum of mutations causing HPRT deficiency: an update. Nucleosides Nucleotides Nucleic Acids. 2004;23:1153-1160.

Lesch M, Nyhan WL. A familial disorder of uric acid metabolism and central nervous system function. Am J Med. 1964;36:561-570.


MIM #248600

□ Who 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.

□ Relevant Tests and Diagnostic Value

Biochemical testing:

  • Quantitative plasma amino acid analysis.

  • Tandem mass spectrometry (MS/MS)-based amino acid profiling. Newborn screening (NBS) programs that employ tandem mass spectrometry detect MSUD.

  • BCKAD enzyme activity.

Molecular diagnostic testing:

  • Gene sequencing and mutation analysis of the three genes: BCKDHA, BCKDHB, and DBT

  • Deletion/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. GeneReviewsTM [Internet]. Seattle, WA: University of Washington, Seattle; 2006:1993-2013 [Updated 2013 May 9]. Available from:


MIM #309400

□ Who Should Be Suspected?

It is a syndrome of neonatal hypothermia, feeding difficulties, and sometimes prolonged jaundice; at 2-3 months, seizures and progressive hair depigmentation and twisting take place. The syndrome also includes a striking facial appearance, increasing mental deterioration, infections, failure to thrive, death in early infancy, and changes in the elastica interna of arteries.

□ Relevant Tests and Diagnostic Value

  • Decreased copper in serum and liver; normal in RBCs; increased copper in amniotic fluid, cultured fibroblasts, and amniotic cells

  • Decreased serum ceruloplasmin

□ Other Considerations

Carrier status for the Menkes disease gene can usually be determined by examination of multiple hairs from scattered scalp sites for pili torti. Changes in the metaphyses of the long bones resemble scurvy. Ascorbic acid oxidase is copper dependent.

Suggested Reading

Moller LB, Bukrinsky JT, Molgaard A, et al. Identification and analysis of 21 novel disease-causing amino acid substitutions in the conserved part of ATP7A. Hum Mutat. 2005;26:84-93.


MIM #261600

□ Relevant Tests and Diagnostic Value

PAH deficiency can be diagnosed by NBS 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 #277900

□ Relevant Tests and Diagnostic Value

  • Low serum ceruloplasmin and/or high urinary copper.

  • Mutation detection: sequence analysis of the entire coding regions; deletion/duplication analysis; targeted mutation analysis.

  • Magnetic resonance imaging (MRI) may show increased signal intensities in the basal ganglia.

Suggested Readings

De Bie P, Muller P, Wijmenga C, et al. Molecular pathogenesis of Wilson and Menkes disease: correlation of mutations with molecular defects and disease phenotypes. J Med Genet. 2007;44:673-688.

Gow PJ, Smallwood RA, Angus PW, et al. Diagnosis of Wilson’s disease: an experience over three decades. Gut. 2000;46:415-419.



MIM #271900

□ Relevant 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.

  • Targeted 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.

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

  • Deletion/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. GeneReviewsTM [Internet]. Seattle, WA: University of Washington, Seattle; 1999:1993-2013 [Updated 2011 Aug 11]. Available from:


MIM #219800

□ Who 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.

□ Relevant Tests and Diagnostic Values

  • Cystine measurement in blood cells, amniotic fluid cells, and chorionic villi.

  • Sequence 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.

  • Fluorescence in situ hybridization (FISH) analysis detects a relatively common 57 kb deletion in the CTNS gene.

□ Other Considerations

  • Kidney 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

□ Relevant Tests and Diagnostic Value

  • Alpha-Galactosidase measurement in blood cells in male patients.

  • Sequence 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.

  • Measurement of globotriaosylceramide (Gb3) increased concentrations of globotriaosylceramide (Gb3).

□ Other 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 Natl Acad Sci U S A. 2008;105:2812-2817.


MIM #22800

□ Classification

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.

□ Relevant Tests and Diagnostic Value

Biochemical testing:

  • Enzyme assay: Acid ceramidase assay of skin fibroblasts.

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

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

Molecular testing:

  • Sequence 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.

Online Mendelian Inheritance in Man. Farber Lipogranulomatosis. John Hopkins University.


MIM #230800

□ Who 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.

□ Classification

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, with rapidly progressive onset in infancy, and affects the brain as well as the systemic 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 occur and can include supranuclear horizontal ophthalmoplegia, progressive myoclonic epilepsy, cerebellar ataxia, spasticity, and dementia, as well as the signs and symptoms seen in type 1.

□ Relevant Tests and Diagnostic Value

Biochemical testing—enzyme assay: Acid beta-glucosidase 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 approximately 90% accurate for identification of carriers.

Molecular testing:

  • Targeted 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.

  • Sequence 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

□ Relevant Tests and Diagnostic Value


  • Fasting blood glucose concentration <60 mg/dL (reference range: 70-120 mg/dL)

  • Blood lactate >2.5 mmol/L (reference range: 0.5-2.2 mmol/L)

  • Blood uric acid >5.0 mg/dL (reference range: 2.0-5.0 mg/dL)

  • Triglycerides >250 mg/dL (reference range: 150-200 mg/dL)

  • Cholesterol >200 mg/dL (reference range: 100-200 mg/dL)

Biochemical testing:

  • Glucose-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).

  • Glucose-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.

  • Targeted mutation analysis:

    • G6PC gene: Arg83Cys and Gln347X or larger panels of mutations

    • SLC37A4 gene: Trp118Arg, 1042_1043delCT, and Gly339Cys

  • Gene sequence analysis:

    • G6PC: 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%.

    • SLC37A4: 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

□ Classification

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

  • Nonclassic infantile onset: Usually presents within the first year of life with motor delays and/or slowly progressive muscle weakness.

  • Late 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.

□ Relevant Tests and Diagnostic Value

Chemical tests:

  • Serum creatine kinase (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.

  • Urinary oligosaccharides: Elevation of a certain urinary glucose tetrasaccharide is highly sensitive in Pompe disease but is also seen in other GSDs. In addition, it may be normal in late-onset disease.

Biochemical testing:

  • Acid α-GAA enzyme activity in cultured skin fibroblasts, whole blood, or dried blood spot (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 lateonset 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.

  • Targeted 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 fullsequence analysis.

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

  • Deletion/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.

□ Other 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

□ Classification

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

  • Type 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.

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

  • Type 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.

□ Relevant Tests and Diagnostic Value

  • Assay of lysosomal acid beta-galactosidase enzyme in leukocytes, cultured fibroblasts, or brain tissue

  • Prenatal diagnosis by enzyme assay in cultured amniotic fluid cells or by HPLC analysis of galactosyl oligosaccharides in amniotic fluid

  • Sequence analysis of gene mutations

□ Other Considerations

  • Tissue 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

□ Relevant Tests and Diagnostic Value

  • Quantitation of total glycosaminoglycans in urine and accumulation of keratan sulfate in tissues.

  • Definitive diagnosis is established by iduronate-2-sulfatase enzyme assay in cultured fibroblasts, leukocytes, amniocytes, or chorionic villi.

  • Sequence analysis of the iduronate-2-sulfatase gene.

□ Other 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

□ Who 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.

□ Relevant Tests and Diagnostic Value

  • Urinary excretion of glycosaminoglycans.

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

  • Sequence 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

□ Who 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.

□ Relevant 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

□ Relevant 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:

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

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

  • Deletion/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.

□ Other Considerations

Conjunctival biopsy shows characteristic ballooned Schwann cells. Brain biopsy shows massive infiltration of unique multinucleated inclusion-containing globoid cells in white matter due to accumulation of galactosylceramide and galactosphingosine, as well as diffuse loss of myelin and 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 Natl Acad Sci U S A. 1974;71:854-857.


MIM #253200

□ Who 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.

□ Relevant Tests and Diagnostic Value

  • Measurement of residual N-acetylgalactosamine-4-sulfatase in fibroblasts

  • Sequence 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

□ Relevant Tests

Biochemical testing:

  • ARSA 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.

  • Urinary excretion of sulfatides: Measured by thin-layer chromatography, HPLC, and/or mass spectrometric techniques. The 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).

  • Metachromatic 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:

  • Targeted 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.

  • Gene 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.

  • Deletion/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.

□ Diagnostic Value

  • Absence of ARSA activity in the urine is useful for early diagnosis.

  • Keratan sulfate is increased in urine (often two to three times normal).

  • Urine sediment may contain metachromatic lipids (from breakdown of myelin products).

□ Other Considerations

Biopsy of sural nerve stained with cresyl violet showing accumulation of metachromatic sulfatide is diagnostic; Sulfatide is 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 Engl J Med. 1991;324:18-22.


MIM #253000

Mar 20, 2021 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Hereditary and Genetic Diseases

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