GM1 and GM2 (Tay-Sachs and Sandhoff diseases) gangliosidoses are rare, autosomal recessive, potentially life-threatening, disabling disorders characterized by progressive neurodegeneration, with no disease-modifying treatment. This qualitative study aimed to understand the humanistic burden of GM1 and GM2 gangliosidoses from caregivers' perspectives by expanding knowledge on the day-to-day responsibilities of primary caregivers and the impacts experienced while providing care and support. Focus groups (90-minute duration) were conducted with caregivers (≥ 18 years) under three separate categories based on the age of the individuals with GM1/GM2 gangliosidoses either in-person (attending Annual National Tay-Sachs & Allied Diseases Association [NTSAD] Conference, Colorado, July 2022) or online (recruited through the NTSAD and Cure GM1 Foundation during November-December 2022). This study included 29 primary caregivers (mean [range] age: 49.0 [37.0-75.0] years) of individuals (children [24.1%], adolescents [31.0%], and adults [44.8%]) diagnosed with juvenile/late-onset GM1 (41.4%) or GM2 (58.6%) gangliosidoses. The caregivers reported that most individuals required mobility aids (64.3%) and experienced speech difficulties (83.3%); they described their caregiving responsibilities as non-stop, pervasive, and often done without additional support, with marginal variance by disease type or patient age. Supporting activities of daily living was the most prominent responsibility (90.0%), followed by symptom/care management (69.0%), ensuring quality of life (45.0%), and maintaining emotional (24.0%) and physical (10.0%) well-being. Caregiving impacted every facet of life; the caregivers reported 25 different impacts, with constant psychological burden (82.8%), physical ailments/strain (62.1%), anxiety/fear/worry (58.6%), financial difficulties (58.6%), limited time for other family members (55.2%), and limitations on relationships outside family (51.7%) having the most significant effects. The caregivers relied mostly on patient advocacy organizations for resources and expressed the need for financial support, broader disease awareness, and disease-modifying treatments. Although providing care and support deleteriously impacted caregivers' lives, they reported experiencing positive impacts on relationship building, personal development, family cohesion, community support, and life outlook. This study showed a substantial humanistic burden with long-term impacts among the caregivers of individuals with GM1 and GM2 gangliosidoses. The findings provide important insights to enhance clinical care while advocating for the resources needed to improve caregivers' and patients' lives.

Tay-Sachs disease (TSD) is a rare and severe neurodegenerative disorder inherited in an autosomal recessive manner. It is caused by a deficiency of the enzyme hexosaminidase A, which is responsible for the degradation of GM2 gangliosides-lipids that accumulate in the nerve cells of the central nervous system. The inability to break down these lipids leads to their progressive accumulation, resulting in irreversible brain damage. Mechanistically, TSD is caused by mutations in the HEXA gene, which encodes the alpha subunit of hexosaminidase A. These mutations disrupt enzyme activity and alter cellular pathways involved in lysosomal lipid degradation. Although Tay-Sachs specifically involves the alpha subunit, similar clinical features can be seen in Sandhoff disease, a related disorder caused by mutations in the HEXB gene, which encodes the beta subunit shared by hexosaminidase A and B. Tay-Sachs is classified into three clinical forms according to age of onset and symptom severity: the classic infantile form, which is the most common and severe; a juvenile (subacute) form; and an adult-onset form, which progresses more slowly and tends to present with milder symptoms. Diagnosis is based on enzymatic testing showing reduced or absent hexosaminidase A activity, confirmed by genetic testing. Prenatal diagnosis and genetic counseling play a key role in prevention and reproductive decision-making, especially in high-risk populations. Although no curative treatment currently exists, ongoing research is exploring gene therapy, enzyme replacement, and pharmacological approaches. Certain compounds, such as gemfibrozil, have shown potential to slow symptom progression. Early diagnosis and multidisciplinary care are essential to improving quality of life, although therapeutic options remain limited due to the progressive nature of the disease.

Late-onset Tay-Sachs disease (LOTS) is a form of GM2 gangliosidosis, an autosomal recessive neurodegenerative disorder characterized by slowly progressive cerebellar ataxia, lower motor neuron disease, and psychiatric impairment due to mutations in the HEXA gene. The aim of our work was to identify the characteristic brain MRI findings in this presumably underdiagnosed disease. Clinical data and MRI findings from 16 patients (10F/6 M) with LOTS from two centers were independently assessed by two readers and compared to 16 age- and sex-related controls. Lower motor neuron disease (94%), psychiatric symptoms-psychosis (31%), cognitive impairment (38%) and depression (25%)-and symptoms of cerebellar impairment including dysarthria (94%), ataxia (81%) and tremor (69%), were the most common clinical features. On MRI, pontocerebellar atrophy was a constant finding. Compared to controls, LOTS patients had smaller mean middle cerebellar peduncle diameter (p < 0.0001), mean superior cerebellar peduncle diameter (p = 0.0002), mesencephalon sagittal area (p = 0.0002), pons sagittal area (p < 0.0001), and larger 4th ventricle transversal diameter (p < 0.0001). Mild corpus callosum thinning (37.5%), mild cortical atrophy (18.8%), and white matter T2 hyperintensities (12.5%) were also present. Given the characteristic clinical course and MRI findings of the pontocerebellar atrophy, late-onset Tay-Sachs disease should be considered in the differential diagnosis of adult-onset cerebellar ataxias.

GM2 gangliosidosis is a neurodegenerative, lysosomal storage disease caused by the deficiency of β-hexosaminidase A enzyme (Hex A), an α/β-subunit heterodimer. A novel variant of the human hexosaminidase α-subunit, coded by HEX M, has previously been shown to form a stable homodimer, Hex M, that hydrolyzes GM2 gangliosides (GM2) in vivo. The current study assessed the efficacy of intravenous (IV) delivery of a self-complementary adeno-associated virus serotype 9 (scAAV9) vector incorporating the HEXM transgene, scAAV9/HEXM, including the outcomes based on the dosages provided to the Sandhoff (SD) mice. Six-week-old SD mice were injected with either 2.5E+12 vector genomes (low dose, LD) or 1.0E+13 vg (high dose, HD). We hypothesized that when examining the dosage comparison for scAAV9/HEXM in adult SD mice, the HD group would have more beneficial outcomes than the LD cohort. Assessments included survival, behavioral outcomes, vector biodistribution, and enzyme activity within the central nervous system. Toxicity was observed in the HD cohort, with 8 of 14 mice dying within one month of the injection. As compared to untreated SD mice, which have typical survival of 16 weeks, the LD cohort and the remaining HD mice had a significant survival benefit with an average/median survival of 40.6/34.5 and 55.9/56.7 weeks, respectively. Significant behavioral, biochemical and molecular benefits were also observed. The second aim of the study was to investigate the effects of IV mannitol infusions on the biodistribution of the LD scAAV9/HEXM vector and the survival of the SD mice. Increases in both the biodistribution of the vector as well as the survival benefit (average/median of 41.6/49.3 weeks) were observed. These results demonstrate the potential benefit and critical limitations of the treatment of GM2 gangliosidosis using IV delivered AAV vectors.

Tay-Sachs disease is a neurodegenerative inherited metabolic disease. There are four forms classified by the time of first clinical symptoms: infantile, late infantile, juvenile and adult. Infantile , Ebru Candab, Ertürk Leventc , The infantile form has the poorest clinical prognosis. First symptoms of this form, such as muscle weakness and hypotonia, occur around form has the poorest prognosis. Lately, different abnormalities which accompany metabolic disorders and affect the prognosis have been described. We present an infant with Tay-Sachs disease accompanied by coarctation of the aorta and bilateral grade V vesicoureteral reflux (VUR). The patient was followed up in the outpatient clinic of Pediatric Cardiology. The abdominal ultrasonography showed pelvicalyceal ectasia; bilateral grade V VUR in voiding cystourethrography was found. This coexistence has not been previously reported. This case emphasizes that abnormalities in the neurological examination of cardiac postsurgical patients should not be underestimated because the opportunity to diagnose inborn errors of metabolism could be missed. La enfermedad de Tay-Sachs es una enfermedad metabólica hereditaria neurodegenerativa. Existen cuatro tipos según el inicio de los síntomas clínicos: infantil, infantil de inicio tardío, juvenil y adulto. El tipo infantil tiene el peor pronóstico. Recientemente, se describieron diferentes anomalías que acompañan a los trastornos metabólicos e influyen en el pronóstico. Presentamos el caso de un lactante con enfermedad de Tay-Sachs junto con coartación aórtica y reflujo vesicoureteral bilateral (RVU) de grado V. Se realizó el seguimiento del paciente en el consultorio externo de Cardiología Pediátrica. En la ecografía abdominal, se observó ectasia pielocalicial, y se detectó reflujo vesicoureteral bilateral de grado V en la cistouretrografía miccional. No se ha informado previamente la coexistencia de estas anomalías. Este caso pone de manifiesto que no se deben subestimar las anomalías del examen neurológico en los pacientes con una cirugía cardíaca reciente, porque podría perderse la oportunidad de diagnosticar enzimopatías congénitas.