Genetic and phenotypic characterization of NKX6-2-related spastic ataxia and hypomyelination.

BACKGROUND AND PURPOSE: Hypomyelinating leukodystrophies are a heterogeneous group of genetic disorders with a wide spectrum of phenotypes and a high rate of genetically unsolved cases. Bi-allelic mutations in NKX6-2 were recently linked to spastic ataxia 8 with hypomyelinating leukodystrophy. METHODS: Using a combination of homozygosity mapping, exome sequencing, and detailed clinical and neuroimaging assessment a series of new NKX6-2 mutations in a multicentre setting is described. Then, all reported NKX6-2 mutations and those identified in this study were combined and an in-depth analysis of NKX6-2-related disease spectrum was provided. RESULTS: Eleven new cases from eight families of different ethnic backgrounds carrying compound heterozygous and homozygous pathogenic variants in NKX6-2 were identified, evidencing a high NKX6-2 mutation burden in the hypomyelinating leukodystrophy disease spectrum. Our data reveal a phenotype spectrum with neonatal onset, global psychomotor delay and worse prognosis at the severe end and a childhood onset with mainly motor phenotype at the milder end. The phenotypic and neuroimaging expression in NKX6-2 is described and it is shown that phenotypes with epilepsy in the absence of overt hypomyelination and diffuse hypomyelination without seizures can occur. CONCLUSIONS: NKX6-2 mutations should be considered in patients with autosomal recessive, very early onset of nystagmus, cerebellar ataxia with hypotonia that rapidly progresses to spasticity, particularly when associated with neuroimaging signs of hypomyelination. Therefore, it is recommended that NXK6-2 should be included in hypomyelinating leukodystrophy and spastic ataxia diagnostic panels.

Autism spectrum disorder in a child with propionic acidemia.

Autism is a neurodevelopmental disorder characterized by a combination of reciprocal social deficits, communication impairment, and rigid ritualistic interests. While autism does not have an identifying cause in most of the cases, it is associated with known medical conditions in at least 10% of cases. Although uncommon, cases of autism have also been reported in association with metabolic disorders. In this brief report, we describe the occurrence of autism in a 7-year-old girl with propionic acidemia (PA), a common form of organic aciduria resulting from the deficiency of propionyl-CoA carboxylase and characterized by frequent and potentially lethal episodes of metabolic acidosis often accompanied by hyperammonemia. It is particularly common in countries with high rates of consanguinity. Early diagnosis of autism in patients with metabolic disorders is important since autistic features are sometimes the most disruptive of all the child's problems. This facilitates providing the needed behavioral services not otherwise available for children with metabolic disorders.

Mode of inheritance in systemic lupus erythematosus in Saudi multiplex families.

Systemic lupus erythematosus (SLE) is a an autoimmune disease causing inflammation and injury of multiple organs like joints, skin, kidneys, eyes, central nervous system, heart. The etiology of SLE remains unknown. However; genetic component significantly contributes to the etiology of SLE. Familial SLE patients were defined as a family with more than one sibling diagnosed with SLE. The objective of the study is to describe the clinical features of the familial SLE and analyze the family pedigrees. Twenty-five individuals with SLE belonging to seven Saudi families were included. Three-generation pedigree was taken from the candidate families. The mean age at onset of the disease was 84.5 months (range: 18-144) while the mean age at diagnosis was 90.6 months (range: 24-144) and the mean duration of follow up was 48.5 months (range: 7-108). The proportion of girls was predominant (78%). Malar rash, arthritis and nephritis were the more frequent features. Sixteen patients had renal lesions, 10 of them had class VI nephritis according WHO classification. Five of the seven families are consanguineous reflecting the high percentage of consanguinity in our population. As many other autoimmune diseases, multifactorial is the most common form of inheritance. In the current study, the suggested mode of inheritance is autosomal recessive assuming Mendelian inheritance of single gene disorder.