Infantile Sandhoff disease with ventricular septal defect: a case report.

BACKGROUND: Infantile Sandhoff disease is a rare inherited disorder that progressively destroys nerve cells in the brain and spinal cord, and is classified under lysosomal storage disorder. It is an autosomal recessive disorder of sphingolipid metabolism that results from deficiency of the lysosomal enzymes ß-hexosaminidase A and B. The resultant accumulation of GM2 ganglioside within both gray matter nuclei and myelin sheaths of the white matter results in eventual severe neuronal dysfunction and neurodegeneration. CASE PRESENTATION: We evaluated a 3.5-year-old Comorian girl from the United Arab Emirates who presented with repeated chest infections with heart failure due to ventricular septal defect, neuroregression, recurrent seizures, and cherry-red spots over macula. She had macrocephaly, axial hypotonia, hyperacusis, and gastroesophageal reflux. Organomegaly was absent. Brain magnetic resonance imaging, metabolic tests, and genetic mutations confirmed the diagnosis. Despite multidisciplinary therapy, the girl succumbed to her illness. CONCLUSION: Though early cardiac involvement can be seen with novel mutations, it is extremely rare to find association of ventricular septal defect in infantile Sandhoff disease. Neuroregression typically starts around 6 months of age. We report this case because of the unusual association of a congenital heart disease with underlying infantile Sandhoff disease and symptomatic heart failure in the first month of life with eventual fatal outcome.

A 23-year follow-up report of juvenile-onset Sandhoff disease presenting with a motor neuron disease phenotype and a novel variant.

BACKGROUND: The clinical severity of Sandhoff disease is known to vary widely. Furthermore, long-term follow-up report is very limited in the literature. CASE PRESENTATION: We present a long-term follow-up report of a patient with juvenile-onset Sandhoff disease with a motor neuron disease phenotype. The patient had compound heterozygous variants of HEXB (p.Trp460Arg, p. Arg533His); the Trp460Arg was a novel variant. Long-term follow-up revealed no intellectual deterioration, swallowing dysfunction, or respiratory muscle dysfunction despite progressive weakness of the extremities and sensory disturbances. CONCLUSION: We need to be aware of Sandhoff disease in patients with juvenile-onset motor neuron disease.

New cases of adult-onset Sandhoff disease with a cerebellar or lower motor neuron phenotype.

Sandhoff disease is a lipid-storage disorder caused by a defect in ganglioside metabolism. It is caused by a lack of functional N-acetyl-beta-d-glucosaminidase A and B due to mutations in the HEXB gene. Typical, early-onset Sandhoff disease presents before 9 months of age with progressive psychomotor retardation and early death. A late-onset form of Sandhoff disease is rare, and its symptoms are heterogeneous. As drug trials that aim to intervene in the disease mechanism are emerging, the recognition and identification of Sandhoff disease patients-particularly those with atypical phenotypes-are becoming more important. The authors describe six new late-onset Sandhoff cases demonstrating cerebellar ataxia or lower motor neuron (LMN) involvement combined with, mostly subclinical, neuropathy. Two different mutations were found: IVS 12-26 G/A and c.1514G-->A. In patients with either progressive cerebellar ataxia or LMN disease in the setting of a possibly recessive disorder, Sandhoff disease should be suspected, even when the onset age is over 45 years.

Substrate reduction therapy with miglustat in chronic GM2 gangliosidosis type Sandhoff: results of a 3-year follow-up.

GM2 gangliosidosis type Sandhoff is caused by a defect of beta-hexosaminidase, an enzyme involved in the catabolism of gangliosides. It has been proposed that substrate reduction therapy using N-butyl-deoxynojirimycin (miglustat) may delay neurological progression, at least in late-onset forms of GM2 gangliosidosis. We report the results of a 3-year treatment with miglustat (100 mg t.i.d) in a patient with chronic Sandhoff disease manifesting with an atypical, spinal muscular atrophy phenotype. The follow-up included serial neurological examinations, blood tests, abdominal ultrasound, and neurophysiologic, cognitive, brain, and muscle MRI studies. We document some minor effects on neurological progression in chronic Sandhoff disease by miglustat treatment, confirming the necessity of phase II therapeutic trials including early-stage patients in order to assess its putative efficacy in chronic Sandhoff disease.

Identification of Sandhoff disease in a Thai family: clinical and biochemical characterization.

Sandhoff disease is a GM2 gangliosidosis that is rare in Thailand. The authors report a Thai family with two children known to have infantile form of Sandhoff disease. The index case exhibited mitral valve prolapse with mitral regurgitation as an early sign, which is a rare presentation in Sandhoff disease. Thereafter the patient had developmental regression, startle reaction, and cherry red spots. The diagnosis was confirmed by biochemical analysis.

Suppression of NK and CD8+ T cells reduces astrogliosis but accelerates cerebellar dysfunction and shortens life span in a mouse model of Sandhoff disease.

Sandhoff disease is an inherited lysosomal storage disease, resulting from the deficiency of lysosomal ß-hexosaminidase A and B enzyme activity. The Hexb-/- mouse model recapitulates human disease and leads to fatal neurodegeneration and neuroinflammation. IL-15 is important for the proliferation of NK, NK T, and CD8+ cytotoxic/memory T cells. In order to determine how changes to IL-15-dependent immune cell populations would alter the course of Sandhoff disease in mice, we generated a Hexb-/-Il-15-/- double knockout mouse and used motor behaviour tests, analyzed peripheral blood and brain leukocyte immunophenotypes, cytokine secretion, as well as examined markers of microgliosis, astrogliosis and apoptosis. Hexb-/-Il-15-/- mice had an accelerated neurodegenerative phenotype, and reached the humane endpoint at 118±3.5d, compared to Hexb-/- mice (127±2.2d). The performance of Hexb-/-Il-15-/- mice declined earlier than Hexb-/- mice on the rotarod and righting reflex motor behaviour tests. Hexb-/- mice had a significantly higher prevalence of pro-inflammatory monocytes in the blood relative to C57BL/6 mice, but this was unaltered by IL-15 deficiency. The prevalence of NK cells and CD8+ T cells in Il-15-/- and Hexb-/-Il-15-/- mice was decreased compared to wild type and Hexb-/- mice. While Hexb-/- mice displayed an increase in the prevalence of CD4+ and CD8+ T cells in brain leukocytes compared to C57BL/6 mice, there was a decrease in CD8+ T cells in Hexb-/-Il-15-/- compared to Hexb-/- mice. In addition, circulating IL-17 and IL-10 levels were significantly higher in Hexb-/-Il-15-/- mice, suggesting heightened inflammation compared to Hexb-/- mice. Interestingly, astrogliosis levels were significantly reduced in the cerebellum of Hexb-/-Il-15-/- mice compared to Hexb-/- mice while microgliosis was not affected in brains of Hexb-/-Il-15-/- mice. Our study demonstrated that IL-15 depletion dramatically reduced numbers of NK and CD8+ T cells as well as astrocytes but accelerated disease progression in Sandhoff mice. These results pointed to interactions between NK/CD8+ T cells and astrogliosis and potentially a protective role for NK/CD8+ T cells and/or astrocytes during disease progression. This observation supports the notion that expanding the IL-15-dependent NK and CD8+ T cells populations with IL-15 therapy may have therapeutic benefits for Sandhoff disease.

Dysautonomic achalasia in two siblings with Sandhoff disease.

Two siblings in their sixth decade with chronic Type II GM2 gangliosidosis developed progressive dysphagia in addition to chronic motor neuron disease and autonomic nervous system (ANS) involvement. Esophageal achalasia was diagnosed in both patients. It is suggested that this esophageal motor disorder may be a manifestation of the neurovegetative system disorder due to alteration of ganglioside metabolism.

Co-existence of phenylketonuria either with maple syrup urine disease or Sandhoff disease in two patients from Iran: emphasizing the role of consanguinity.

Most inborn errors of metabolism (IEMs) are inherited in an autosomal recessive manner. IEMs are one of the major concerns in Iran due to its extensive consanguineous marriages. Herein, we report two patients with two co-existent IEMs: a girl affected by classic phenylketonuria (PKU) and maple syrup urine disease (MSUD) and a male patient affected with Sandhoff disease and PKU, where Sandhoff disease was suspected due to the presence of a cherry-red spot in the eyes at 6 months which is unrelated to PKU. Sequencing of candidate genes in the first patient revealed one novel and three recurrent compound heterozygous mutations of p.Ser231Pro and p.Ala300Ser in the PAH gene and p.Glu330Lys and p.Arg170Cys mutations in the BCKDHB gene. Genetic testing results in the second patient showed previously reported homozygous mutations of p.Arg261Gln in the PAH and p.Arg533Cys mutation in the HEXB gene. Genetic testing confirmed the clinical diagnosis of both diseases in both patients. To the best of our knowledge; this is the first report of the co-existence of two distinct genetic disorders in two individuals from Iran. Co-existent different IEMs in patients complicated the clinical diagnosis and management of the diseases.

"Cherry-red spot" or "perifoveal white patch"?

The color of the normal fovea, red in Caucasians, contrasts with the surrounding retina, whose colour is altered by accumulation of metabolic products, causing retinal pallor. In this photo-essay, we present the fundus photographs of 3 patients of different race, all with metabolic disease, each of whose fovea contrasts with the surrounding retina, and for whom the expression "cherry red spot" is not necessarily accurate. We suggest that the term "perifoveal white patch" describes this characteristic finding more accurately. We also discuss the pathological entities that may produce this striking appearance, along with its histological and anatomical basis.

Late-onset GM2 gangliosidosis presenting as burning dysesthesias.

Two brothers with a painful neuropathy as a component of late-onset GM2 gangliosidosis of the Sandhoff type are presented. A dramatic response of the severe dysesthesias to amitriptyline and gabapentin is described. Symptomatic sensory neuropathy may be a component of late-onset GM2 gangliosidosis.

Development of infertility at young adult age in a mouse model of human Sandhoff disease.

Sandhoff disease is a human lysosomal storage disease. In a knockout mouse model of Sandhoff disease, which lacks the beta-subunit of beta-hexosaminidase A (Hex A, alphabeta subunits) and B (Hex B, betabeta subunits), the mutant homozygous mice (Hexb(-/-)) are healthy until 15 weeks of age when they develop neurodegenerative symptoms. This study was designed to analyse the fertility profile of male and female Hexb(-/-) mice. Mating behaviour of Hexb(-/-) mice was assessed at different ages. The ovarian function of Hexb(-/-) females was determined by superovulation studies. The quality of spermatozoa and ova was assessed by an in vitro fertilization (IVF) procedure. Hexb(-/-) mice were fertile at a young age. Males were fertile up to the age of 69.3 +/- 6.3 days (mean +/- SD) and females were fertile up to the age of 56-63 days. Since both the Hexb (-/-) sexes showed fertility, the results indicate that Hex A and Hex B (major isozymes of beta-hexosaminidase) may not be required for sperm-ovum interactions, in contrast to the widely accepted belief. On the other hand, young adult Hexb(-/-) males showed a reduction in mating behaviour at the age of 84.8 +/- 2.2 days and an absence of mating behaviour at 94.2 +/- 2.0 days. Spermatozoa from Hexb(-/-) mice (aged 109.2 +/- 1.8 days) showed a lower IVF rate. Among Hexb (-/-) females aged 85.6 +/- 2.1 days, no mice became pregnant although they were positive for a vaginal plug when caged with fertile males. The number of ova recovered from Hexb(-/-) females (aged 111.0 +/- 3.1 days) and the IVF rate of ova were lower than those of controls. In conclusion, Hex A and Hex B may not be required for sperm-ovum interactions. Mice lacking Hex A and Hex B activities develop infertility at a young adult age in an age-dependent manner.

Sandhoff disease (GM2 Gangliosidoses) in a premature patient with bronchopulmonary dysplasia.

We report a female premature infant with bronchopulmonary dysplasia and Sandhoff disease. The clue for diagnosis was the fundoscopy examination. We discuss this rare disease with unusual presentation of intrauterine growth retardation, premature delivery, and bronchopulmonary dysplasia.

[Adult Sandhoff disease presented as a motor neuron disease phenotype with slow progression].

A 35-year old Japanese male with adult Sandhoff disease was described, who was presented as a motor neuron disease phenotype with slow progression. At the age of 15, he first noticed weakness in his thigh. At the age of 28, his upper and lower motor neuron disturbances were disclosed. He was diagnosed as atypical amyotrophic lateral sclerosis. At the age of 34, a slight sensory disturbance appeared in the lower extremities. When he was admitted to our hospital, he displayed marked atrophy and weakness in his quadriceps femoris muscles, but no signs of mental deterioration and cerebellar ataxia. Because of the atypical course of motor neuron disease, hexosaminidase activity in peripheral leukocytes was determined. The assay of total hexosaminidase, hexosaminidase A and hexosaminidase B activities demonstrated low levels of these activities (7-15% of controls), leading the diagnosis of Sandoff disease. He was a member of non-consanguineous family, and the abnormal patterns of hexasaminidase activities were different between his father and mother. These data appear to show that he is a compound heterozygote in the locus of the hexosaminidase B gene. This is the first Japanese case of adult Sanhoff disease presented as a motor neuron disease phenotype.

[A case of juvenile Sandhoff disease].

A Japanese male with juvenile Sandhoff disease is described. The patient was a product of full-term normal pregnancy from non-consanguineous parents. Since age 10, he developed progressive dysarthria and proximal muscle atrophy and weakness. Mental deterioration and cerebellar ataxia are also noted since the age of 20. On neurological examination at age 35, he showed decreased mentality (IQ 62), marked atrophy and weakness of proximal muscles, cerebellar ataxia and increased deep tendon reflexes. Brain CT scans revealed moderate to marked atrophy of cerebellum. Giant MUP, fasciculation potentials and positive sharp waves were observed on EMG examination. Biopsied sural nerve showed markedly decreased myelinated fibers. Hexosaminidase A and B activities in leukocytes and cultured fibroblasts were about 10% of normal values, while other lysosomal enzyme activities were within normal range. Rectal biopsy demonstrated lamellar inclusion bodies in submucosal ganglion cells. This is the first Japanese patient with juvenile Sandhoff disease presenting symptoms similar to motor neuron disease and cerebellar degeneration.

Homozygous p.R284* mutation in HEXB gene causing Sandhoff disease with nystagmus.

Sandhoff disease is a rare, genetic, lipid storage disorder characterized by progressive degeneration of the nerve cells (neurons) in the brain and spinal cord. This disease is caused by mutations in the beta-hexosaminidase beta-subunit (HEXB) gene. Here, we investigated the clinical characteristics and molecular basis of Sandhoff disease in an infant female patient from Jordan. The initial sign was nystagmus, which was noted at birth. To our knowledge, this is the first report of Sandhoff disease from Jordan. Introducing lysosomal enzyme assays to the testing of children with global developmental delay with unknown etiology in countries with high rates of consanguinity will not only increase the percentage of diagnosed cases, but will also help orient genetic counseling and prenatal diagnosis and eventually will reduce the overall burden of disabilities in these countries.

Infantile Sandhoff's disease with peripheral neuropathy.

Sandhoff's disease is a rare autosomal-recessive disorder of sphingolipid metabolism that results from a deficiency of lysosomal enzyme beta-hexosaminidase A and B. The resultant accumulation of GM2 gangliosides within both grey matter and the myelin sheath of white matter results in essential, severe neurodegeneration. We describe a 14-month-old boy with seizures and severe neurodegeneration. His diagnosis was confirmed by neuroimaging and enzyme assay. In addition to the classic features of Sandhoff's disease, the child's clinical features were suggestive of neuropathy as supported by nerve conduction studies indicating that the bilateral median, ulnar, and common peroneal nerves were affected. Peripheral nervous system involvement is not consistently observed in infantile Sandhoff's disease, prompting us to report this case.