PURPOSE: The purpose of this study was to describe the phenotype (and corresponding genotype) of adult patients with late-onset Tay-Sachs disease, a clinical variant of the GM2-gangliosidoses. METHODS: A comprehensive physical examination, including neurological assessments, was performed to establish the current disease pattern and severity. In addition, the patients' past medical histories were reviewed. The patients' alpha-subunit mutations (beta-Hexosaminidase A genotype) were determined and correlated with their corresponding clinical findings and disease course. RESULTS: Twenty-one patients (current mean age: 27.0 years; range: 14-47 years) were identified. The pedigree revealed a relative with the "classic" infantile or late-onset form of Tay-Sachs disease in four (out of 18) unrelated families. The patients were predominantly male (15/21 individuals) and of Ashkenazi Jewish ancestry (15/18 families). Mean age at onset was 18.1 years; balance problems and difficulty climbing stairs were the most frequent presenting complaints. In several cases, the diagnosis was delayed (mean age at diagnosis: 27.0 years). Analysis of the beta-hex A gene revealed the G269S mutation as the most common disease allele; found in homozygosity (N = 1) or heterozygosity (N = 18; including 2 sib pairs). Disease onset (age 36 years) was delayed and progression relatively slower in the homozygous G269S patient. Two siblings (ages 28 and 31 years), of non-Jewish ancestry, were compound heterozygotes (TATC1278/W474C); their clinical course is dominated by psychiatric problems. Brain imaging studies revealed marked cerebellar atrophy in all patients (N = 18) tested, regardless of disease stage. CONCLUSIONS: Late-onset Tay-Sachs disease is an infrequent disorder and the diagnosis is often missed or delayed (by approximately 8 years). Early on, the majority of patients develop signs of either cerebellar or anterior motor neuron involvement. Affected individuals may also develop psychotic episodes. In most cases, the later-onset of expression results from the presence of at least one allele (usually the G269S mutation), associated with residual enzyme (beta-hexosaminidase A) activity. A positive family history is a valuable clue, enabling early diagnosis. Nonspecific cerebellar atrophy on brain imaging is another important finding. This entity should be considered among patients presenting with speech, gait, and balance problems, and those with psychiatric disorders even when focal neurologic deficits may be initially absent. Accurate diagnosis will permit appropriate genetic counseling regarding disease prognosis and reproductive risks.

Tay-Sachs disease (a GM2 gangliosidosis) is an inherited neuronal storage disease that can affect individuals across the age spectrum. Psychosis is reported in 30% to 50% of adult-onset patients, and many are misdiagnosed with schizophrenia. Mood disorders are present in more than 25% and cognitive impairment in more than 20%. Treatment of psychosis with neuroleptics may not have a favorable risk/benefit ratio, but treatment with benzodiazepines or electroconvulsive therapy may be efficacious. Metabolic diseases such as gangliosidosis are probably under-recognized as causes of neuropsychiatric illness. Increased awareness of these disorders will lead to accurate diagnosis, appropriate treatment selection, and genetic counseling.

Neuro-ophthalmology of late-onset Tay-Sachs disease (LOTS).Neurology. 2004 Nov 23;63(10):1918-26.

BACKGROUND: Late-onset Tay-Sachs disease (LOTS) is an adult-onset, autosomal recessive, progressive variant of GM2 gangliosidosis, characterized by involvement of the cerebellum and anterior horn cells. OBJECTIVE: To determine the range of visual and ocular motor abnormalities in LOTS, as a prelude to evaluating the effectiveness of novel therapies. METHODS: Fourteen patients with biochemically confirmed LOTS (8 men; age range 24 to 53 years; disease duration 5 to 30 years) and 10 age-matched control subjects were studied. Snellen visual acuity, contrast sensitivity, color vision, stereopsis, and visual fields were measured, and optic fundi were photographed. Horizontal and vertical eye movements (search coil) were recorded, and saccades, pursuit, vestibulo-ocular reflex (VOR), vergence, and optokinetic (OK) responses were measured. RESULTS: All patients showed normal visual functions and optic fundi. The main eye movement abnormality concerned saccades, which were "multistep," consisting of a series of small saccades and larger movements that showed transient decelerations. Larger saccades ended earlier and more abruptly (greater peak deceleration) in LOTS patients than in control subjects; these changes can be attributed to premature termination of the saccadic pulse. Smooth-pursuit and slow-phase OK gains were reduced, but VOR, vergence, and gaze holding were normal. CONCLUSIONS: Patients with late-onset Tay-Sachs disease (LOTS) show characteristic abnormalities of saccades but normal afferent visual systems. Hypometria, transient decelerations, and premature termination of saccades suggest disruption of a "latch circuit" that normally inhibits pontine omnipause neurons, permitting burst neurons to discharge until the eye movement is completed. These measurable abnormalities of saccades provide a means to evaluate the effects of novel treatments for LOTS.

Tay Sachs disease carrier screening in schools: educational alternatives and cheekbrush sampling.Genet Med. 2005 Nov-Dec;7(9):626-32.

PURPOSE: Tay Sachs disease carrier screening programs have been offered successfully worldwide since 1970. The programs typically offer education, testing, and counseling to provide reproductive choices. One such program has been offered to Jewish school students in Melbourne since 1998. In a time of increasing public awareness of genetics, programs require continuous evaluation and updating. METHODS: Over 2 successive years, a longitudinal evaluation involved students attending Jewish schools in Melbourne. Both qualitative and quantitative techniques were used to analyze alternative methods for education and sampling procedures. Comparisons involved (1) a computer-based resource versus an oral educational presentation and (2) blood sampling for enzyme and genetic testing versus cheekbrush testing for genetic sampling alone. RESULTS: The education session was effective in significantly increasing students' knowledge (10.5% +/- 1.2%, P < .0001) and decreasing their anxiety about being a carrier (-12.2% +/- 1.6%, P < .0001). For the students, no significant differences were found between the computer-based resource and oral presentation. There were significantly more students accepting a carrier test and anxiety was lower when a cheekbrush test was offered compared with when a blood test was offered. CONCLUSIONS: Computer-based instruction is equally effective, in addition to offering advantages of self-paced learning and minimization of human resources as an oral presentation within a genetic carrier screening program. Cheekbrush sampling is preferred to blood sampling and should be implemented into current practices for offering genetic screening programs. These results present alternatives to practices for genetic screening reflecting the current developing technology.

The history of human genetic lysosomal disorders began in 1881 with the description of what is now known as Tay-Sachs disease. In the early 1960s, when I entered the field while I was a neurology resident, the first phase of studies of lysosomal disorders was being replaced with the second analytical biochemistry phase. Saul Korey, the first Chairman of the Department of Neurology, Albert Einstein College of Medicine, initiated the first integrated approach with a team consisting of clinical neurologists, neuropathologists, electron microscopists, cell biologists, organic chemists, and enzymologists. Despite his tragic death in 1963 in his mid-forties, the field flourished along the line of his vision through the third enzymology phase to the fourth and current molecular biology phase. The concept of Tay-Sachs disease as the only ganglioside storage disease has expanded to two forms of gangliosidoses, GM1- and GM2-gangliosidoses, and the latter into three distinct genetic disorders. Tay-Sachs disease, Sandhoff disease and the GM2 activator protein deficiency. More recently, all three genes coding for the three proteins each responsible for distinct genetic forms of GM2-gangliosidosis--beta-hexosaminidase alpha and beta subunits and the GM2 activator protein--have been cloned and many disease-causing mutations have been identified. We have reached the halfway point in our quest for eventual understanding of the pathogenesis and effective treatment of these disorders, starting from the clinical phenotype through biochemistry to the gene. With this new knowledge on the gene level, we should be tracing the route back to enzymology, biology and pathogenetic mechanism of these disorders in the years to come.