Case: Alonso-Perez_Patient 2, Female, 41yo, Spanish

DiseaseAssertion: Sandhoff Disease

CasePresentingHPOs: HP:0000007, HP:0001260

CaseHPOFreeText:

CaseNOTHPOs: HP:0002380, HP:0001324, HP:0003202

CaseNOTHPOFreeText: No signs of cerebellar or sensory dysfunction, deep tendon reflexes were normal

CasePreviousTesting: Nerve conduction studies and EMG were performed with normal results. Serum CK levels were tested and found to be elevated with the rest of the biochemical analysis normal. MRI was normal with no involvement of the brain. Serum β-hexosaminidase-enzyme activity assay showed low levels.

GenotypingMethod: Sanger sequencing of SMN1, DYNC1H1 and BICD2 genes showed no pathogenic variants. WES revealed HEXB mutations.

PreviouslyPublished: n/a

SupplementalData: n/a

Variant: NM_000521.4, c.171delG (p.Trp57Cysfs7)

CAID: CA3305751

gnomAD: MAF: unavailable in gnomAD, gnomAD variant ID: 5-73981254-TG-T

VariantEvidence: This variant is known to be pathogenic and was previously published only in infantile cases of SD, PMID: 22789865. Total hexosaminidase activity in fibroblasts from the patients with this variant in that paper range from 2.3-9.5% of the normal control levels.

MultipleGeneVariants AR, allele on second allele

Variant: c.1510C>T (p.Pro504Ser)

CAID: CA116493

gnomAD: MAF: 0.0002259, Latino/admixed American, gnomad variant ID: 5-74016469-C-T

VariantEvidence: This variant is known to be pathogenic and was previously published in adult cases of SD, PMID: 9694901. This study concluded the effect of the mutation on ganglioside hydrolysis, combined with its effect on intracellular transport, produces chronic Sandhoff disease.

Case: Alonso-Perez_Patient 1, Male, 46yo, Spanish

DiseaseAssertion: Sandhoff Disease

CasePresentingHPOs: HP:0000007, HP:0002380, HP:0001260, HP:0001324, HP:0003202

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText: No signs of cerebellar involvement, cranial nerves appeared normal

CasePreviousTesting: Nerve conduction studies and EMG were performed with normal results from nerve conduction studies but active and chronic denervation revealed by EMG. Serum CK levels were tested and found to be elevated with the rest of the biochemical analysis normal. MRI was normal with no involvement of the brain, but whole-body MRI revealed fatty replacement along with areas of healthy muscles in both quadriceps. Muscle biopsy showed neurogenic changes with angulated and atrophic fibers. Results from all previous tests suggested a diagnosis of lower motor neuron disease. Serum β-hexosaminidase-enzyme activity assay showed low levels.

GenotypingMethod: Sanger sequencing of SMN1, DYNC1H1 and BICD2 genes showed no pathogenic variants. WES revealed HEXB mutations.

PreviouslyPublished: n/a

SupplementalData: n/a

Variant: NM_000521.4, c.171delG (p.Trp57Cysfs7)

CAID: CA3305751

gnomAD: MAF: unavailable in gnomAD, gnomAD variant ID: 5-73981254-TG-T

VariantEvidence: This variant is known to be pathogenic and was previously published only in infantile cases of SD, PMID: 22789865. Total hexosaminidase activity in fibroblasts from the patients with this variant in that paper range from 2.3-9.5% of the normal control levels.

MultipleGeneVariants AR, allele on second allele

Variant: c.1510C>T (p.Pro504Ser)

CAID: CA116493

gnomAD: MAF: 0.0002259, Latino/admixed American, gnomad variant ID: 5-74016469-C-T

VariantEvidence: This variant is known to be pathogenic and was previously published in adult cases of SD, PMID: 9694901. This study concluded the effect of the mutation on ganglioside hydrolysis, combined with its effect on intracellular transport, produces chronic Sandhoff disease

PMID: 29106755

Gene: HEXB

Disease: Sandhoff Disease

MonDO: MONDO:0010006

Case: Zampieri SD1, Male

DiseaseAssertion: Sandhoff Disease

FamilyInfo: patient's genotype was confirmed in parents

CasePresentingHPOs: HP:0000007, HP:0033978

CaseHPOFreeText: neurological symptoms (unspecified)

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: Patients presented with neurological symptoms and diagnosis was confirmed by the demonstration of reduced Hex A and Hex B activity in peripheral white blood cells or cultured fibroblasts.

GenotypingMethod: PCR

PreviouslyPublished: n/a

SupplementalData: n/a

Variant: c.534delAGTT (p.L178fs27X) in both alleles

CAID: CA560766108

gnomAD: MAF 0.000008937, European (non-Finnish), gnomAD variant ID: 5-73992535-CAGTT-C

VariantEvidence: PMID:11292324 previously reported this variant to be associated with the infantile form of SD. Genomic DNA amplification, heteroduplex analysis, cloning and sequencing revealed a 4-bp deletion in exon 4 at position 178. The result is a frameshift mutation that leads to a stop codon in exon 5. This mutation is associated with a dramatic decrease of HEXB mRNA levels.

Case: Zampieri SD2, Male

DiseaseAssertion: Sandhoff Disease

FamilyInfo: patient's genotype was confirmed in parents

CasePresentingHPOs: HP:0000007, HP:0033978

CaseHPOFreeText: neurological symptoms (unspecified)

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: Patients presented with neurological symptoms and diagnosis was confirmed by the demonstration of reduced Hex A and Hex B activity in peripheral white blood cells or cultured fibroblasts.

GenotypingMethod: PCR

PreviouslyPublished: n/a

SupplementalData: n/a

Variant: c.850C>T (p.R284X) on allele 1

CAID: CA116495

gnomAD: MAF: 0.0002286 South Asian, gnomAD variant ID: 5-74009409-C-T

VariantEvidence: PMID:8162015 previously reported this variant to be associated with the infantile form of SD. A fibroblast line from this patient with the infantile form of the disease was investigated for mutations by single strand conformation polymorphism analysis and direct sequencing of PCR products. A nonsense mutation was found which generated a stop codon at codon 284. The study investigated the steady-state level of mRNA produced by cells containing stop codons using a competitive polymerase chain reaction technique and found that at codon 284, the mRNA levels were 0.8%, as percent of normal per single gene dose.

MultipleGeneVariants: AR, different variant in second allele

GeneName: HEXB

Variant: c.1613+2T>G (p.E538ins4X5) on allele 2

CAID: CA3306214

gnomAD: MAF: 0.000008808, European (non-Finnish), gnomAD ID: 5-74016574-T-G

VariantEvidence: PMID: 8535449 previously reported this variant to be associated with the infantile form of SD. This study found the total Hex activity to be 8% of the normal level, with only 0.5% being hex B which was reported to be insignificant. This intronic mutation affects the 5' donor site of intron 13 and results in insertion of 48 nucleotides which shifts the reading frame and results in the generation of a PTC.

Case: Zampieri SD4, Male

DiseaseAssertion: Sandhoff Disease

FamilyInfo: patient's genotype was confirmed in parents

CasePresentingHPOs: HP:0000007, HP:0033978

CaseHPOFreeText: neurological symptoms (unspecified)

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: Patients presented with neurological symptoms and diagnosis was confirmed by the demonstration of reduced Hex A and Hex B activity in peripheral white blood cells or cultured fibroblasts.

GenotypingMethod: PCR

PreviouslyPublished: n/a

SupplementalData: n/a

Variant: c.850C>T (p.R284X) same on both alleles

CAID: CA116495

gnomAD: MAF: 0.0002286 South Asian, gnomAD variant ID: 5-74009409-C-T

VariantEvidence: PMID:8162015 previously reported this variant to be associated with the infantile form of SD. A fibroblast line from this patient with the infantile form of the disease was investigated for mutations by single strand conformation polymorphism analysis and direct sequencing of PCR products. A nonsense mutation was found which generated a stop codon at codon 284. The study investigated the steady-state level of mRNA produced by cells containing stop codons using a competitive polymerase chain reaction technique and found that at codon 284, the mRNA levels were 0.8%, as percent of normal per single gene dose.

Case: Zampieri SD5, Female

DiseaseAssertion: Sandhoff Disease

FamilyInfo: patient's genotype was confirmed in parents

CasePresentingHPOs: HP:0000007, HP:0033978

CaseHPOFreeText: neurological symptoms (unspecified)

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: Patients presented with neurological symptoms and diagnosis was confirmed by the demonstration of reduced Hex A and Hex B activity in peripheral white blood cells or cultured fibroblasts.

GenotypingMethod: PCR

PreviouslyPublished: n/a

SupplementalData: n/a

Variant: c.1372C>T (p.Q458X) same on both alleles

CAID: CA360070432

gnomAD: not found in gnomAD

VariantEvidence: This mutation is novel and results in the introduction of a premature stop codon at position 458 that would lead to a truncated protein. This study proved the functional relevance in vivo by conducting a RT-PCR analysis of the HEXB mRNA which detected the mutated HEXB mRNA.

Case: Zampieri SD9, Female

DiseaseAssertion: Sandhoff Disease

FamilyInfo: patient's genotype was confirmed in parents

CasePresentingHPOs: HP:0000007, HP:0033978

CaseHPOFreeText: neurological symptoms (unspecified)

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: Patients presented with neurological symptoms and diagnosis was confirmed by the demonstration of reduced Hex A and Hex B activity in peripheral white blood cells or cultured fibroblasts.

GenotypingMethod: PCR

PreviouslyPublished: n/a

SupplementalData: n/a

Variant: c.850C>T (p.R284X) same on both alleles

CAID: CA116495

gnomAD: MAF: 0.0002286 South Asian, gnomAD variant ID: 5-74009409-C-T

VariantEvidence: PMID:8162015 previously reported this variant to be associated with the infantile form of SD. A fibroblast line from this patient with the infantile form of the disease was investigated for mutations by single strand conformation polymorphism analysis and direct sequencing of PCR products. A nonsense mutation was found which generated a stop codon at codon 284. The study investigated the steady-state level of mRNA produced by cells containing stop codons using a competitive polymerase chain reaction technique and found that at codon 284, the mRNA levels were 0.8%, as percent of normal per single gene dose.

PMID: 31140649

Gene: HEXB

Disease: Sandhoff Disease

MonDO: MONDO:0010006