Spastic Tetraplegia, Thin Corpus Callosum, And Progressive Microcephaly

A number sign (#) is used with this entry because of evidence that spastic tetraplegia, thin corpus callosum, and progressive microcephaly (SPATCCM) is caused by homozygous or compound heterozygous mutation in the SLC1A4 gene (600229) on chromosome 2p14.

Description

Spastic tetraplegia, thin corpus callosum, and progressive microcephaly is an autosomal recessive neurodevelopmental disorder characterized by onset of those features and severely impaired global development in early infancy. Most patients are unable to achieve independent walking or speech; some patients have seizures (summary by Srour et al., 2015 and Heimer et al., 2015).

Clinical Features

Srour et al. (2015) reported 2 sibs, born of consanguineous Ashkenazi Jewish parents, with a severe neurodevelopmental disorder characterized by delayed psychomotor development with lack of speech and inability to walk, postnatal progressive microcephaly, and spasticity that was worse in the lower limbs. One sib had febrile seizures in infancy. Brain imaging of both children showed thin corpus callosum, delayed myelination, and nonspecific white matter abnormalities. The patients did not have dysmorphic features. Srour et al. (2015) noted the phenotypic similarities to patients with L-serine biosynthesis disorders (see, e.g., PSPHD, 614023).

Heimer et al. (2015) reported 2 unrelated children with significant global developmental delay, severe progressive microcephaly (up to -4 SD), seizures, spasticity, and thin corpus callosum. A 4.5-year-old girl of Ashkenazi Jewish descent showed delayed development from early infancy and had onset of tonic and myoclonic seizures at age 11 months. She was unable to walk and had no eye contact or speech. In addition to thin corpus callosum, brain imaging showed delayed myelination and cerebral atrophy. A 6-year-old girl, born of Ashkenazi-Iraqi parents, had global developmental delay since infancy and onset of febrile seizures at age 1 year. She was able to walk with assistance, had eye contact, and could babble. Both patients showed hyperreflexia, extensor plantar responses, irritability, hyperactivity, sleep disorder, and stereotypic behavior.

Damseh et al. (2015) reported 10 children from 8 families of Ashkenazi Jewish descent with SPATCCM. In infancy, the patients had hypotonia and global developmental delay. They later showed progressive microcephaly, spasticity, and absent or very poor language. Five patients developed seizures ranging from simple febrile to intractable epilepsy with hypsarrhythmia. Brain imaging was variable, but showed thin corpus callosum, decreased myelination, and/or cerebral atrophy in most patients. Another patient, born of consanguineous Palestinian parents, was also described; she had an even more severe phenotype, with hip dysplasia and poor visual responses with reduced electroretinogram.

Inheritance

The transmission pattern of spastic tetraplegia, thin corpus callosum, and progressive microcephaly in the families reported by Srour et al. (2015) and Damseh et al. (2015) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 sibs, born of consanguineous Ashkenazi Jewish parents, with SPATCCM, Srour et al. (2015) identified a homozygous missense mutation in the SLC1A4 gene (E256K; 600229.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Srour et al. (2015) proposed that disruption of SLC1A4 impairs brain development and function by decreasing the availability of L-serine in neurons.

Heimer et al. (2015) identified a homozygous E256K mutation in the SLC1A4 gene in a 4.5-year-old girl of Ashkenazi Jewish descent with SPATCCM. An unrelated girl of Ashkenazi-Iraqi descent with the disorder was compound heterozygous for E256K and a truncating mutation (600229.0002). Functional studies of the variants were not performed.

Damseh et al. (2015) identified a homozygous E256K mutation in 9 patients from 7 unrelated families of Ashkenazi Jewish descent with SPATCCM. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in all families. Haplotype analysis indicated that the E256K mutation was a founder mutation in the Ashkenazi Jewish population. In vitro functional expression studies in HEK cells showed that L-serine and L-alanine transport by the E256K variant was reduced by 25% and 20%, respectively, compared to wildtype. Another patient, born of an Ashkenazi Jewish father and an Iraqi-Jewish mother, was compound heterozygous for the E256K mutation and a frameshift mutation (600229.0002). A different homozygous missense mutation in the SLC1A4 gene (R457W; 600229.0003) was found in a girl, born of consanguineous Palestinian parents, with SPATCCM. In vitro functional expression studies in HEK cells showed no measurable substrate transport activity for the R457W variant.

Population Genetics

The carrier frequency of the SLC1A4 founder mutation E256K among Ashkenazi Jewish controls has been estimated to be 0.0056 (Srour et al., 2015) and 0.007 (Damseh et al., 2015).