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Genotype and phenotype classification of 29 patients affected by Krabbe disease.

ABSTRACT: Krabbe disease is a rare neurodegenerative lysosomal storage disorder caused by mutations in the galactocerebrosidase gene, GALC. Krabbe disease usually affects infants, but has also been reported in older children and adults. Different phenotypes are described based on age at onset. The gene encoding the galactocerebrosidase enzyme was cloned and expressed in 1993, and up until today 117 mutations have been described. In a patient population of Northern European origin, a 30-kb deletion and two missense mutations, c.1586C>T; p.T529M and c.1700A>C; p.Y567S, are expected to account for 50%-60% of pathogenic alleles. In this study, we present information on genetic variation, enzyme activity, and phenotypes of 29 patients affected by Krabbe disease. Patient data were collected from patient files at the Department of Clinical Genetics, Rigshospitalet. Ten previously unreported mutations were identified, including four missense mutations; c.1142C>T; p.T381I, c.596G>T; p.R199M, c.443G>A; p.G148E, c.1858G>A; p.G620R, two nonsense mutations; c.863G>A; p.W288*, c.1214c>G; p.S405*, one splice site mutation; c.442+1G>A, one insertion; c.293insT and two deletions; c.1003_1004del, c.887delA. For all of the new mutations, we were able to classify them in phenotype groups. Furthermore, we present a combined allele frequency of the three frequent mutations p.T529M, p.Y567S, and the 30-kb deletion of 62%, and we describe a broadening of the phenotypes associated with the mutations p.T529M and p.Y567S.

SUBMITTER: Madsen AMH

PROVIDER: S-EPMC6498822 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Genotype and phenotype classification of 29 patients affected by Krabbe disease.

Madsen Anna M H AMH Wibrand Flemming F Lund Allan M AM Ek Jakob J Dunø Morten M Østergaard Elsebet E

JIMD reports 20190314 1

Krabbe disease is a rare neurodegenerative lysosomal storage disorder caused by mutations in the galactocerebrosidase gene, <i>GALC</i>. Krabbe disease usually affects infants, but has also been reported in older children and adults. Different phenotypes are described based on age at onset. The gene encoding the galactocerebrosidase enzyme was cloned and expressed in 1993, and up until today 117 mutations have been described. In a patient population of Northern European origin, a 30-kb deletion ...[more]

PMID: 31240153

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Project description:AIM:To determine the mutational characterization of P-type ATP7B gene and to explore the correlation of ATP7B genotype to phenotype in Chinese patients with Wilson disease (WD). METHODS:Seventy-five patients with WD from 72 no-kinship families, 44 males and 31 females, were enrolled in this study. The age of onset ranged from 4 to 39 years, <=18 years in 72 patients. Some exons of ATP7B gene mutations were analyzed in patients with WD by using biochemical methods, polymerase chain reaction-single strand configuration polymorphism (PCR-SSCP) and DNA sequence analysis. A total of 778 coding regions were identified with restriction enzyme Msp I. The activity of Cu-ATPase was assessed by measuring inorganic phosphorus. RESULTS:Sixty-six of 75 patients (88%) had with hepatic manifestations, 39 of them had only hepatic manifestations, 27 patients had hepatic and neurological manifestations or other symptoms at the same time (16 patients had associated neurological manifestation, 3 patients had osteopathy, 8 patients had other symptoms). Eight of the 75 patients (10.7%) had only neurological symptoms, one patient (5 years old) had no symptom. Twelve changing patterns were detected in ATP7B gene by DNA sequencing, including seven mutations (R778L, C656X, G943D, V1140A, V1106I V1216M and 1384del17), six polymorphisms (IVS4-5t/c, A2495G, C2310G, IVS18+6c/t and IVS20+5a/g). R778L occurred in 49/66 patients (74%) with hepatic manifestations, homozygosis of R778L in 16 patients, heterozygosity of R778L in 33 patients. V1106I mutation of ATP7B gene occurred in 2 patients with delaying onset of clinical symptoms. Cu-ATPase activity of three patients with known mutations (R778L/V1106I/A2495G, R778L/V1216M and R778L/R778L) were determined, and the activity of Cu-ATPase was decreased by 44.55%, 88.23% and 69.49% respectively. CONCLUSION:1384del17bp is a novel mutation found in WD patients. R778L is the most common mutation of ATP7B gene. There is a correlation between R778L and hepatic manifestations in WD patient.

Project description:BackgroundPhelan-McDermid syndrome (PMS) or 22q13 deletion syndrome is a rare developmental disorder characterized by hypotonia, developmental delay (DD), intellectual disability (ID), autism spectrum disorder (ASD) and dysmorphic features. Most cases are caused by 22q13 deletions encompassing many genes including SHANK3. Phenotype comparisons between patients with SHANK3 mutations (or deletions only disrupt SHANK3) and 22q13 deletions encompassing more than SHANK3 gene are lacking.MethodsA total of 29 Mainland China patients were clinically and genetically evaluated. Data were obtained from medical record review and a standardized medical history questionnaire, and dysmorphology evaluation was conducted via photographic evaluation. We analyzed 22q13 deletions and SHANK3 small mutations and performed genotype-phenotype analysis to determine whether neurological features and other important clinical features are responsible for haploinsufficiency of SHANK3.ResultsNineteen patients with 22q13.3 deletions ranging in size from 34 kb to 8.7 Mb, one patient with terminal deletions and duplications, and nine patients with SHANK3 mutations were included. All mutations would cause loss-of function effect and six novel heterozygous variants, c.3838_3839insGG, c.3088delC, c.3526G > T, c.3372dupC, c.3120delC and c.3942delC, were firstly reported. Besides, we demonstrated speech delay (100%), DD/ID (88%), ASD (80%), hypotonia (83%) and hyperactivity (83%) were prominent clinical features. Finally, 100% of cases with monogenic SHANK3 deletion had hypotonia and there was no significant difference between loss of SHANK3 alone and deletions encompassing more than SHANK3 gene in the prevalence of hypotonia, DD/ID, ASD, increased pain tolerance, gait abnormalities, impulsiveness, repetitive behaviors, regression and nonstop crying which were high in loss of SHANK3 alone group.ConclusionsThis is the first work describing a cohort of Mainland China patients broaden the clinical and molecular spectrum of PMS. Our findings support the effect of 22q13 deletions and SHANK3 point mutations on language impairment and several clinical manifestations, such as DD/ID. We also demonstrated SHANK3 haploinsufficiency was a major contributor to the neurological phenotypes of PMS and also responsible for other important phenotypes such as hypotonia, increased pain tolerance, impulsiveness, repetitive behaviors, regression and nonstop crying.

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Genotype and phenotype classification of 29 patients affected by Krabbe disease.

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Genotype and phenotype classification of 29 patients affected by Krabbe disease.

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