Tay Sachs disease
Toro C, Shirvan L, Tifft C. HEXA Disorders. 1999 Mar 11 [Updated 2020 Oct 1]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1218/
clinical phenotypes
acute infantile TSD
subacute juvenile TSD
late-onset TSD
beta-hexosaminidase A deficiency, HEXA disorder
pathogenesis
hexosaminidase A (HEX A) degrades GM2 ganglioside
without degradation, GM2 gangliosides accumulate in lysosomes of CNS and peripheral neurones
Progressive weakness and loss of motor skills beginning between ages three and six months
Decreased attentiveness, unusual eye movements
An increased or exaggerated startle response
A cherry-red spot of the fovea centralis of the macula of the retina
A normal-sized liver and spleen
Generalized muscular hypotonia with sustained ankle clonus and hyperreflexia, myoclonic jerks
Onset of seizures beginning around age 12 months
Progressive macrocephaly with proportionate ventricular enlargement on neuroimaging beginning at age 18 months
A period of normal development until ages two to five years followed by a plateauing of skills and then loss of previously acquired developmental skills
Progressive spasticity resulting in loss of independent ambulation
Progressive dysarthria, drooling, and eventually absent speech
Normal-sized liver and spleen
Onset of seizures
Progressive global brain atrophy on neuroimaging
Onset of symptoms in teens or adulthood, variable phenotypes
Progressive neurogenic weakness of antigravity muscles in the lower extremities and frequent falls, years later triceps weakness
Dysarthria, tremor, and incoordination, progressive dystonia
Acute psychiatric manifestations including psychosis (which can be the initial manifestation of disease) - can be initial manifestation!
Isolated cerebellar atrophy on neuroimaging
HEX A heterodimer 1 alpha + 1 beta subunit (genes: HEXA, HEXB)
HEX B: homodimer 2 beta subunits
GM2 gangliozide only degraded by HEX A
diagnosis
absent/low HEX A acitivity - serum, leukocyte, other tissue
biallelic pathogenic/likely pathogenic variant in HEXA
onset before 6 mo, rapid progression, death <5 y
later onset, survival until late childhood/adolescense
developmental plateau 6-10 mo, progressive loss of skills, vision deteriorates, decererebrate posturing, difficulty swallowing, woresning seizures, vegetative state
vegetative state 10-15 y
sphingolipidosis