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Letter response: Intra-familial phenotype variability in Late-Onset Tay-Sachs disease


Giulietta Maria Riboldi ,

The Marlene and Paolo Fresco Institute for Parkinson’s Disease and Movement Disorders, New York University Langone Health, New York, NY; Department of Neurology, New York University Langone Health, New York, NY, US
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Heather Lau

Department of Neurology, New York University Langone Health, New York, NY; Yale University, Department of Internal Medicine, US
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How to Cite: Riboldi GM, Lau H. Letter response: Intra-familial phenotype variability in Late-Onset Tay-Sachs disease. Tremor and Other Hyperkinetic Movements. 2023;13(1):6. DOI:
  Published on 22 Feb 2023
 Accepted on 07 Feb 2023            Submitted on 03 Feb 2023

We thank Lefter and Ryan for the interesting comment to our manuscript. We agree with their observation in regards of the interfamilial phenotypic variability within subjects with Late Onset Tay-Sachs (LOTS) disease.

In order to strength this observation, we further reviewed the cases reported in the literature and that were included in our publication. As we reported in our manuscript, a positive family history of LOTS was present in 58.8% of subjects presenting with a mainly neuromuscular phenotype, 75% of subjects with a predominant cerebellar phenotype, 37.5% of subjects with prevalent psychiatric manifestation, and 83.3% of subjects with a predominant stuttering phenotype [1].

As noted in Navon et al., 1986, one of the initial works reporting familial cases of LOTS stated that “affected relatives of the same family had a rather uniform clinical picture” [2]. However, as the same authors comment later on in the manuscript and as suggested by Lefter and Ryan (2022), this has not been necessarily confirmed in the following literature [2].

Consistently with the above observations, we reviewed the manuscripts where the clinical history of probands and their relatives was detailed and we found a spectrum of clinical presentations within families. In particular, some of the works reported very similar phenotypic presentation (i.e. predominant neurological and psychiatric manifestations) as well as a similar progression and severity of symptoms over time within affected members of the same family [2, 3, 4, 5, 6, 7]. In some families, the phenotype was similar (i.e. predominant cerebellar or stuttering phenotype at presentation) but the age of onset within different individuals in the same family and the progression of the symptoms was different [3, 8]. Other authors described, instead, a significant intra-familial variability in the reported cases, both in terms of clinical presentation and timeline of symptom onset [2, 3, 9, 10, 11, 12, 13].

The genotype was not consistently reported for all these cases, so it is not possible to speculate about a role of different genetic variants in the context of intra-familial variability. Interestingly, Willner et al., 1981 reported one family with two affected identical twins presenting an overlapping phenotype and disease progression, while the two other affected siblings in the same family presented a similar clinical phenotype but a different rate of progression of their symptoms [3].

We thank Lefter and Ryan for their clarification regarding this point raised by our manuscript and we believe that these additional observations will further enrich the content of our paper and our understanding of LOTS.

Financial Disclosures

HL is Full time employee of Ultragenyx Therapeutics. This work received no support form Ultragenyx Therapeutics.

GMR has no financial disclosure.

Competing Interests

The authors have no competing interests to declare.


  1. Riboldi GM, Lau H. Diagnostic Tips from a Video Series and Literature Review of Patients with Late-Onset Tay-Sachs Disease. Tremor Other Hyperkinet Mov (N Y). 2022; 12: 34. DOI: 

  2. Navon R, Argov Z, Frisch A. Hexosaminidase A deficiency in adults. Am J Med Genet. 1986 May; 24(1): 179–96. DOI: 

  3. Willner JP, Grabowski GA, Gordon RE, Bender AN, Desnick RJ. Chronic GM2 gangliosidosis masquerading as atypical Friedreich ataxia: clinical, morphologic, and biochemical studies of nine cases. Neurology. 1981 Jul; 31(7): 787–98. DOI: 

  4. Rapin I, Suzuki K, Suzuki K, Valsamis MP. Adult (chronic) GM2 gangliosidosis. Atypical spinocerebellar degeneration in a Jewish sibship. Arch Neurol. 1976 Feb; 33(2): 120–30. DOI: 

  5. Hund E, Grau A, Fogel W, Forsting M, Cantz M, Kustermann-Kuhn B, et al. Progressive cerebellar ataxia, proximal neurogenic weakness and ocular motor disturbances: hexosaminidase A deficiency with late clinical onset in four siblings. J Neurol Sci. 1997 Jan; 145(1): 25–31. DOI: 

  6. Rubin M, Karpati G, Wolfe LS, Carpenter S, Klavins MH, Mahuran DJ. Adult onset motor neuronopathy in the juvenile type of hexosaminidase A and B deficiency. J Neurol Sci. 1988 Oct; 87(1): 103–19. DOI: 

  7. Harding AE, Young EP, Schon F. Adult onset supranuclear ophthalmoplegia, cerebellar ataxia, and neurogenic proximal muscle weakness in a brother and sister: another hexosaminidase A deficiency syndrome. J Neurol Neurosurg Psychiatry. 1987 Jun; 50(6): 687–90. DOI: 

  8. Grim KK, Phillips GD, Renner DR. Dysarthria and Stutter as Presenting Symptoms of Late-Onset Tay-Sachs Disease in Three Siblings. Mov Disord Clin Pract. 2015 Sep; 2(3): 289–90. DOI: 

  9. Karni A, Navon R, Sadeh M. Hexosaminidase A deficiency manifesting as spinal muscular atrophy of late onset. Ann Neurol. 1988 Sep; 24(3): 451–3. DOI: 

  10. Argov Z, Navon R. Clinical and genetic variations in the syndrome of adult GM2 gangliosidosis resulting from hexosaminidase A deficiency. Ann Neurol. 1984 Jul; 16(1): 14–20. DOI: 

  11. Rozenberg R, Pereira L da V. The frequency of Tay-Sachs disease causing mutations in the Brazilian Jewish population justifies a carrier screening program. Sao Paulo Med J. 2001 Jul 5; 119(4): 146–9. DOI: 

  12. Johnson WG, Wigger HJ, Karp HR, Glaubiger LM, Rowland LP. Juvenile spinal muscular atrophy: a new hexosaminidase deficiency phenotype. Ann Neurol. 1982 Jan; 11(1): 11–6. DOI: 

  13. Lefter S, O’ Mahony O, Sweeney B, Ryan AM. Late-Onset Tay-Sachs Disease in an Irish Family. Mov Disord Clin Pract. 2021 Jan; 8(1): 106–10. DOI: 

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