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