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Phenotypic and mutational spectrum of 17 Chinese patients with Menkes Disease
Fang Xu1, Hongyan Huang1, Qiuyan Shen1
1Department of Neurology, West China Hospital, Sichuan University, Chengdu, China.
Background:
Menkes Disease (MD) is a fatal X-linked recessive disorder caused by mutations in the ATP7A gene. Severe cases typically die before the age of three. Mild MD and occipital horn syndrome are variants of MD characterized by a less severe phenotype and longer survival.
Objective:
This case series aims to validate previous findings, expand the clinical phenotype, identify novel ATP7A mutations of MD patients.
Methods:
Observational data with follow-up were collected from 17 genetically diagnosed Chinese MD patients.
Results:
All 17 patients exhibited neurological symptoms, including delayed motor milestones (100%) and seizures (58.8%). Unspecific pregnancy or delivery complications occurred in 9 patients (52.9%). The most prevalent connective tissue problems were abnormal hair (76.5%), followed by skeletal and dental abnormalities (52.9%), skin problems (41.2%) and hernia (35.3%). Sensorineural hearing loss (17.6%) was previously unreported. Coronary artery aneurysm and patent foramen ovale (5.9%) were infrequent. One 16-year-old boy carries pathological exon 3-4 deletion, presents novel mild phenotype including short stature and cerebellar ataxia. Out of 13 patients with follow-up (median: 24 months), 7 patients (53.8%) died with median survival of 40 months (range: 21-48 months), 3 patients (23.1%) show severe motor development delay and 2 (15.4%) have refractory epilepsy, only the mild MD patient shows improved cerebellar ataxia. Sixteen ATP7A mutations were identified including 6 small indels (37.5%), 5 nonsense mutations (31.2%), 2 missense mutations (12.5%), 2 exon deletions (12.5%), and 1 splice site mutation (6.25%). Fourteen mutations were novel.
Conclusions:
Our study further broadens the phenotypic and genotypic spectrums of Menkes disease.
Insights
Menkes disease (MD) is a severe X-linked disorder caused by ATP7A mutations. This study expands the known phenotypes and genotypes of MD, identifying novel mutations and highlighting previously unreported symptoms like hearing loss.
Area of Science:
- Genetics and Molecular Biology
- Pediatric Neurology
- Rare Diseases
Background:
- Menkes disease (MD) is a fatal X-linked recessive disorder resulting from ATP7A gene mutations.
- Severe MD typically leads to death before age three, while milder forms and occipital horn syndrome present with less severe phenotypes and longer survival.
Purpose of the Study:
- To validate previous findings on Menkes disease.
- To expand the understanding of the clinical phenotype associated with MD.
- To identify novel ATP7A mutations in patients diagnosed with MD.
Main Methods:
- Observational data collection with patient follow-up.
- Genetic diagnosis of 17 Chinese patients with Menkes disease.
- Analysis of clinical symptoms, connective tissue abnormalities, and molecular genetic data.
Main Results:
- All 17 patients displayed neurological symptoms, including delayed motor milestones (100%) and seizures (58.8%).
- Common connective tissue issues included abnormal hair (76.5%) and skeletal/dental abnormalities (52.9%). Sensorineural hearing loss was a newly reported finding (17.6%).
- Sixteen ATP7A mutations were identified, with 14 being novel. Survival ranged up to 48 months, with significant motor delays and refractory epilepsy observed in survivors.
Conclusions:
- This study broadens the known phenotypic and genotypic spectrum of Menkes disease.
- Novel ATP7A mutations and previously unreported clinical features, such as sensorineural hearing loss, were identified.
- The findings contribute to a more comprehensive understanding of MD's genetic and clinical variability.
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