Neurodevelopmental Disorder With Seizures And Speech And Walking Impairment

A number sign (#) is used with this entry because of evidence that neurodevelopmental disorder with seizures and speech and walking impairment (NEDSSWI) is caused by compound heterozygous mutation in the DHPS gene (600944) on chromosome 19p13.

Description

Neurodevelopmental disorder with seizures and speech and walking impairment (NEDSSWI) is an autosomal recessive disorder with onset in infancy. Patients show global developmental delay, particularly of speech acquisition, as well as walking difficulties due to hypotonia, hypertonia, spasticity, or poor coordination. Other features include seizures, mild dysmorphic features, and variable short stature. The pregnancies tend to be complicated by hyper- or hypotension (summary by Ganapathi et al., 2019).

Clinical Features

Ganapathi et al. (2019) reported 5 patients, including 2 sibs, with a neurodevelopmental disorder. Four of the patients were 5 to 9 years of age, whereas 1 (patient 5) was 24 years of age. All patients were of mixed mainly Northern European ancestry. The pregnancies had various complications, including HELLP syndrome (see 189800), pregnancy-induced hypertension, preeclampsia, oligohydramnios, and/or low blood pressure. The sibs showed nuchal translucency, and 2 unrelated patients were born prematurely at 32 and 34 weeks' gestation. The patients had global developmental delay with mildly delayed walking between 14 and 30 months and more severely delayed speech/language development: 2 patients, including the 24-year-old woman, were nonverbal. Three patients had behavioral problems, such as hand flapping or pica. Additional notable features included hypotonia and walking difficulties due to balance problems, instability, or spasticity. The 24-year-old woman was wheelchair-bound and had no bladder control. Two females had short stature, and 1 had microcephaly. Four patients had variable clinical seizures, and 1 had staring spells. EEG showed variable abnormalities, such as focal discharges or frequent spike waves, but these changes did not always correlate with clinical seizures. Brain imaging was normal. Mild dysmorphic features included deep-set eyes, prominent infraorbital creases, and medial eyebrow flare; more variable features included thin upper lip, high-arched palate, low-set ears, prominent nasal bridge, and fifth finger clinodactyly. Other variable features included constipation and cold hands. The 2 sibs had sacral dimples, easy bruising, skin sensitivity, and low IgA and IgG levels, associated with recurrent infections in 1 patient.

Inheritance

The transmission pattern of NEDSSWI in the families reported by Ganapathi et al. (2019) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 5 patients from 4 unrelated families of European descent with NEDSSWI, Ganapathi et al. (2019) identified compound heterozygous mutations in the DHPS gene (600944.0001-600944.0004). All patients carried a heterozygous N173S missense variant (600944.0001) on 1 allele and either a splice site mutation, in-frame deletion, or point mutation disrupting the initiation codon on the other allele. The mutations, which were found by exome sequencing, segregated with the disorder in the families. After identification of the first family, the subsequent families were ascertained through GeneMatcher. Haplotype analysis suggested a possible distant common ancestor for the N173S variant in 3 of the families. In vitro functional expression studies of the purified enzyme in E. coli showed that the N173S and Y305_I306del (600944.0003) variants, both of which affected highly conserved residues, had decreased enzyme activity manifest as impaired biosynthesis of deoxyhypusine compared to wildtype, with the Y305_I306del variant being almost completely devoid of enzyme activity. The N173S variant retained some partial activity (about 18 to 25% of wildtype). These findings were verified by further studies of hypusination of eIF5A (600187) in HEK293 cells, which was significantly decreased by both variants, with a more severe effect by Y305_I306del.