Key Points
Disease summary:
The hereditary spastic paraplegias (HSPs) are genetically heterogeneous disorders in which progressive difficulty walking due to spastic weakness of both legs is the predominant neurologic syndrome.
HSP clinical syndromes may be limited to difficulty walking due to lower extremity spastic weakness (“uncomplicated HSP”) or may include other neurologic or systemic disturbances (“complicated HSP”).
There may be wide variability in age-of-symptom onset, rate of worsening, degree of disability, and presence (and severity) of additional of neurologic involvement both within and between different genetic types of HSP.
Neuropathologic analyses of uncomplicated HSP generally reveals degeneration of corticospinal tract axons that is maximal in the thoracic spinal cord; degeneration of fasciculus gracilis fibers that is maximal in the cervicomedullary region; and a degree of demyelination that is considered to be secondary to axon degeneration.
Proteins encoded by HSP genes have diverse functions including mitochondrial function, axon transport, microtubule processing, protein folding and chaperone, endoplasmic reticulum morphology, and myelin structure.
Hereditary basis:
More than 50 genetic types of HSP have been described (Table 134-1). Autosomal dominant, autosomal recessive, X-linked forms of HSP are each genetically heterogeneous. In addition, HSP due to ATP6 gene mitochondrial gene mutation (and therefore, with maternally inherited HSP) has been recently described.
Differential diagnosis:
Many different conditions have overlapping signs and symptoms. The differential diagnosis should include structural abnormalities of the brain and spinal cord, leukodystrophies, inflammatory disorders, metabolic disturbances, and infection.
Table 134-1 Genetic Types of HSP (updated from Fink JK, 2011)
| Spastic Gait (SPG) Locus | OMIM Number | Protein (genetic locus if protein is unknown) | Clinical Syndrome |
|---|---|---|---|
| Autosomal dominant HSP | |||
| SPG3A | 182600 | Atlastin | Uncomplicated HSP: symptoms usually begin in childhood (and may be nonprogressive); symptoms may also begin in adolescence or adulthood and worsen insidiously. Genetic non-penetrance reported. De novo mutation reported presenting as spastic diplegic cerebral palsy. |
| SPG4 | 128601 | Spastin | Uncomplicated HSP, symptom onset in infancy through senescence, single most common cause of autosomal dominant HSP (~40%); some subjects have late-onset cognitive impairment. |
| SPG6 | 600363 | Not imprinted in Prader-Willi/Angelman 1 (NIPA1) | Uncomplicated HSP: prototypical late-adolescent, early-adult onset, slowly progressive uncomplicated HSP |
| SPG8 | 603563 | KIAA0196/strumpellin | Uncomplicated HSP |
| SPG9 | 601162 | (10q23.3-q24.2) | Complicated: spastic paraplegia associated with cataracts, gastroesophageal reflux, and motor neuronopathy |
| SPG10 | 604187 | Kinesin heavy chain (KIF5A) | Uncomplicated HSP or complicated by distal muscle atrophy |
| SPG12 | 604805 | Reticulon 2 (RTN2) | Uncomplicated HSP |
| SPG13 | 605280 | Chaperonin 60 (heat shock protein 60, HSP60) | Uncomplicated HSP: adolescent and adult onset |
| SPG17 | 270685 | BSCL2/seipin | Complicated: spastic paraplegia associated with amyotrophy of hand muscles (Silver Syndrome) |
| SPG19 | 607152 | (9q33-q34) | Uncomplicated HSP |
| SPG29 | 609727 | (1p31.1-21.1) | Complicated: spastic paraplegia associated with hearing impairment; persistent vomiting due to hiatal hernia inherited |
| SPG31 | 610250 | Receptor expression enhancing protein 1 (REEP1) | Uncomplicated HSP or occasionally associated with peripheral neuropathy |
| SPG33 | 610244 | ZFYVE27/protrudin | Uncomplicated HSP |
| SPG36 | 613096 | (12q23-24) | Onset age 14 to 28 years, associated with motor sensory neuropathy |
| SPG37 | 611945 | (8p21.1-q13.3) | Uncomplicated HSP |
| SPG38 | 612335 | (4p16-p15) | One family, 5 affected subjects, onset age 16-21 years. Subjects had atrophy of intrinsic hand muscles (severe in one subject at age 58) |
| SPG40 | (No OMIM #) | (Locus unknown) | Uncomplicated spastic paraplegia, onset after age 35, known autosomal dominant HSP loci excluded |
| SPG41 | 613364 | (11p14.1-p11.2) | Single Chinese family with adolescent onset, spastic paraplegia associated with mild weakness of intrinsic hand muscles |
| SPG42 | 612539 | Acetyl CoA transporter (SLC33A1) | Uncomplicated spastic paraplegia reported in single kindred, onset age 4-40 years, possibly one instance of incomplete penetrance |
| Autosomal recessive HSP | |||
| SPG5 | 270800 | CYP7B1 | Uncomplicated or complicated by axonal neuropathy, distal or generalized muscle atrophy, and white matter abnormalities on MRI |
| SPG7 | 607259 | Paraplegin | Uncomplicated or complicated: variably associated with mitochondrial abnormalities on skeletal muscle biopsy and dysarthria, dysphagia, optic disc pallor, axonal neuropathy, and evidence of “vascular lesions”, cerebellar atrophy, or cerebral atrophy on cranial MRI |
| SPG11 | 604360 | Spatacsin (KIAA1840) | Uncomplicated or complicated: spastic paraplegia variably associated with thin corpus callosum, mental retardation, upper extremity weakness, dysarthria, and nystagmus; may have “Kjellin syndrome”: childhood onset, progressive spastic paraplegia accompanied by pigmentary retinopathy, mental retardation, dysarthria, dementia, and distal muscle atrophy; juvenile, slowly progressive ALS reported in subjects with SPG11 HSP; 50% of autosomal recessive HSP is considered to be SPG11 |
| SPG14 | 605229 | (3q27-28) | Single consanguineous Italian family, 3 affected subjects, onset age ~30 years; complicated spastic paraplegia with mental retardation and distal motor neuropathy (sural nerve biopsy was normal) |
| SPG15 | 270700 | Spastizin/ZFYVE26 | Complicated: spastic paraplegia variably associated with pigmented maculopathy, distal amyotrophy, dysarthria, mental retardation, and further intellectual deterioration (Kjellin syndrome). |
| SPG18 | 611225 | ERLIN2 | Three families described. One with childhood-onset intellectual and motor disability and contractures; one with and spastic paraplegia complicated by mental retardation and thin corpus callosum; one with spastic paraplegia, mental retardation, and epilepsy |
| SPG20 | 275900 | Spartin | Complicated: spastic paraplegia associated with distal muscle wasting (Troyer syndrome) |
| SPG21 | 248900 | Maspardin | Complicated: spastic paraplegia associated with dementia, cerebellar and extrapyramidal signs, thin corpus callosum, and white matter abnormalities (Mast syndrome) |
| SPG23 | 270750 | (1q24-q32) | Complicated: childhood-onset HSP associated with skin pigment abnormality (vitiligo), premature graying, characteristic facies; Lison syndrome |
| SPG24 | 607584 | (13q14) | Complicated: childhood-onset HSP variably complicated by spastic dysarthria and pseudobulbar signs |
| SPG25 | 608220 | (6q23-q24.1) | Consanguineous Italian family, four subjects with adult (30-46 year)-onset back and neck pain related to disk herniation and spastic paraplegia; surgical correction of disk herniation ameliorated pain and reduced spastic paraplegia. Peripheral neuropathy also present. |
| SPG26 | 609195 | (12p11.1–12q14) | Single consanguineous Bedouin family with five affected subjects. Complicated: childhood onset (between 7 and 8 years), progressive spastic paraparesis with dysarthria and distal amyotrophy in both upper and lower limbs, nerve conduction studies were normal; mild intellectual impairment, normal brain MRI. |
| SPG27 | 609041 | (10q22.1-q24.1) | Complicated or uncomplicated HSP. Two families described. In one family (7 affected subjects) uncomplicated spastic paraplegia began between ages 25 and 45 years. In the second family (three subjects described) the disorder began in childhood and included spastic paraplegia, ataxia, dysarthria, mental retardation, sensorimotor polyneuropathy, facial dysmorphism, and short stature. |
| SPG28 | 609340 | (14q21.3-q22.3) | Uncomplicated: childhood-onset progressive spastic gait |
| SPG29 | 609727 | (14q) | Uncomplicated HSP, childhood onset |
| SPG30 | 610357 | (2q37.3) | Complicated: spastic paraplegia, distal wasting, saccadic ocular pursuit, peripheral neuropathy, mild cerebellar signs |
| SPG32 | 611252 | (14q12-q21) | Mild mental retardation, brainstem dysraphia, clinically asymptomatic cerebellar atrophy |
| SPG35 | 612319 | Fatty acid 2-hydroxylase (FA2H) | Childhood onset (6-11 years), spastic paraplegia with extrapyramidal features, progressive dysarthria, dementia, seizures. Brain white matter abnormalities and brain iron accumulation; an Omani and a Pakistani kindred reported. |
| SPG39 | 612020 | Neuropathy target esterase (NTE) | Complicated: spastic paraplegia associated with wasting of distal upper and lower extremity muscles |
| SPG43 | (No OMIM #) | C19orf12 | Two sisters from Mali, symptom onset 7 and 12 years, progressive spastic paraplegia with atrophy of intrinsic hand muscles and dysarthria (one sister) |
| SPG44 | 613206 | Gap junction protein GJA12/GJC2, also known as connexin47 (Cx47) | Allelic with “Pelizaeus-Merzbacher-like disease“ (PMLD, early-onset dysmyelinating disorder with nystagmus, psychomotor delay, progressive spasticity, ataxia). GJA/GJC2 mutation I33M causes a milder phenotype: late-onset (first and second decades), cognitive impairment, slowly progressive, spastic paraplegia, dysarthria, and upper extremity involvement. MRI and MR spectroscopy imaging consistent with a hypomyelinating leukoencephalopathy |
| SPG45 | 613162 | (10q24.3-q25.1) | Single consanguineous kindred from Turkey, five subjects described: affected subjects had mental retardation, infantile onset lower extremity spasticity and contractures, one subject with optic atrophy, two subjects with pendular nystagmus; MRI in one subject was normal. |
| SPG46 | 614409 | (9p21.2-q21.12) | Dementia, congenital cataract, ataxia, thin corpus callosum |
| SPG47 | See 603513 | AP4B1 | Two affected siblings from consanguineous Arabic family with early childhood onset slowly progressive spastic paraparesis, mental retardation, and seizures; one subject had ventriculomegaly; the other subject had thin corpus callosum and periventricular white matter abnormalities |
| SPG48 | 613647 | KIAA0415 | Analysis of KIAA0415 gene in 166 unrelated spastic paraplegia subjects (38 recessive, 64 dominant, 64 “apparently sporadic”) and control subjects revealed homozygous mutation in two siblings with late onset (6th decade) uncomplicated spastic paraplegia; and heterozygous mutation in one subject with apparently sporadic spastic paraplegia. |
| “SPOAN” syndrome | 609541 | (11q23) | Complicated: spastic paraplegia, optic atrophy, neuropathy (SPOAN) |
| No SPG designation | 256840 | Epsilon subunit of the cytosolic chaperonin-containing t-complex peptide-1 (Cct5) | |
