Natural history and genotype-phenotype correlation of pantothenate kinase-associated neurodegeneration.

Xuting Chang,Jie Zhang,Ye Wu,Yuwu Jiang,Jingmin Wang

doi:10.1111/cns.13294

Xuting Chang, Jie Zhang + Show 3 more

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https://doi.org/10.1111/cns.13294

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Abstract

AimsTo investigate the natural history and genotype‐phenotype correlation of pantothenate kinase‐associated neurodegeneration.MethodsWe collected data of patients with PKAN by searching from available publications in English and Chinese. Patients diagnosed in our center (Peking University First Hospital) were also included. The difference in natural history and genotype between early‐onset (<10 year of age at onset) and late‐onset patients (≥10 year of age at onset) with PKAN was compared.ResultsA total of 248 patients were included. The median age at onset was 3.0 years in the early‐onset group and 18.0 years in the late‐onset group. Dystonia in lower limbs was the most common initial symptom in both groups. In the early‐onset group, the median interval between the disease onset and occurrence of oromandibular dystonia, generalized dystonia, loss of independent ambulance was 6.0 years, 5.0 years, and 5.0 years. The corresponding values in late‐onset group were 1.0 year, 4.0 years, and 6.0 years. About 20.0% died at median age of 12.5 years and 9.5 years after the onset in early‐onset group. About 2.0% of the late‐onset patients died during the follow‐up. A total of 176 mutations were identified. Patients carrying two null alleles in PANK2 showed significantly earlier age of disease onset and progressed more rapidly to loss of independent ambulance.ConclusionsThis study provided a comprehensive review on the natural history and genotype of 248 patients with PKAN. The results will serve as a historical control data for future clinical trial on PKAN.

Highlights

Pantothenate kinase-associated neurodegeneration (PKAN, OMIM#234200, formerly known as Hallervorden-Spatz syndrome), called neurodegeneration with brain iron accumulation1 (NBIA1), is the main form of NBIA.[1]
The proportion of patients who progressed to oromandibular dystonia, generalized dystonia, and even loss of independent ambulance was much higher in early-onset patients
As for the genotype-phenotype correlation, we demonstrated that patients with two null alleles in PANK2 showed significantly earlier age of disease onset and progressed more rapidly to loss of independent ambulance

Summary

| INTRODUCTION

Pantothenate kinase-associated neurodegeneration (PKAN, OMIM#234200, formerly known as Hallervorden-Spatz syndrome), called neurodegeneration with brain iron accumulation. Classic patients are usually characterized by dystonia before 10 years of age and loss of ambulation 10-15 years after onset. Atypical patients are characterized by dystonia and dysarthria after 10 years of age, and they cannot walk. We summarized the natural history and genotypic spectrum of 248 patients with PKAN by searching and analyzing the data from available publications. We compared the differences in natural history and genotype between early-onset and late-onset patients with PKAN. Patients who met all the following criteria were enrolled: (a) dystonia; (b) “eye-of-the-tiger” sign on brain MRI; and (c) biallelic pathogenic or likely pathogenic variants in PANK2. The following information of the patients was collected: basic information (gender, age, and country), symptoms at onset and during the progression, examination (fundus, cranial MRI, and cranial CT), and mutations in PANK2 in each individual. Patients were divided into early-onset (

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Findings

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