Table 4.

Genetic Disorders in the Differential Diagnosis of Late-Onset Sandhoff Disease

GeneDiffDx DisorderMOIClinical Features of DiffDx Disorder
Overlapping w/late-onset SDDistinguishing from late-onset SD
AR Spinal & bulbar muscular atrophy XLNeurogenic weakness/atrophy (proximal > distal), tremor, cramps & fasciculations, slow progressionTongue atrophy, facial weakness, androgen insensitivity, gynecomastia, & glucose intolerance
C9orf72
FUS
SOD1
TARDBP
(>30 genes) 1		 Amyotrophic lateral sclerosis AD
AR
XL		Progressive neurogenic atrophy, cramps & fasciculations, spasticityNeurogenic atrophy often asymmetric; bulbar onset (in some persons); absence of cerebellar deficits
CLN6
CTSF
DNAJC5 		Adult-onset neuronal ceroid lipofuscinosis (OMIM 204300, 615362, 162350)AR
AD		AtaxiaSeizures, myoclonus, & early intellectual deterioration
FXN Friedreich ataxia ARAtaxia, abnormal eye movements, dysarthria, neurogenic weakness & long tract findings, slow progressionCardiomyopathy, EKG conduction defects, diabetes, pes cavus, scoliosis, slow sensory nerve conduction velocity, optic atrophy, hearing loss, & neurogenic bladder
HEXA Tay-Sachs disease (See HEXA Disorders.)ARSimilar clinical course w/prominent progressive motor neuronopathy starting in lower extremitiesDysarthria, ataxia tends to be more prominent with more severe cerebellar atrophy; more sensory symptoms & dysautonomia than in SD; psychosis may be presenting manifestation
PMP22
(>80 genes)		 Charcot-Marie-Tooth hereditary neuropathy AD
AR
XL		Progressive weakness, muscle atrophy, sensory ataxiaDysarthria; ataxia is sensory rather than cerebellar; motor neuron involvement
SMN1 Later-onset spinal muscular atrophy (SMA types III & IV)ARTremor, fasciculations, atrophy, cramps, proximal muscle involvementEarly scoliosis, tongue fasciculations, progressive ↓ in pulmonary function, & absence of ataxia
CHCHD10
TFG
VAPB 		Late-onset SMA (See CHCHD10-Related Disorders.) & SMA-like disorder (OMIM 604484, 182980)ADNeurogenic atrophyIn large kindreds, no cerebellar deficits

AD = autosomal dominant; AR = autosomal recessive; DiffDx = differential diagnosis; EKG = electrocardiogram; MOI = mode of inheritance; SD = Sandhoff disease; XL = X-linked

1.

C9orf72, FUS, SOD1, and TARDBP are the most commonly involved genes; for other genes associated with amyotrophic lateral sclerosis, see OMIM Phenotypic Series: Amyotrophic lateral sclerosis.

From: Sandhoff Disease

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