Genetic mutation in pontocerebellar hypoplasia

To the Editor : Pontocerebellar hypoplasias (PCH) is a heterogeneous group of rare autosomal recessive disorders characterized by a fetal onset of an abnormally small cerebellum and brainstem without significant disorganization of the brain architectures (1–5). The diagnosis of PCH is usually made clinically by features such as microcephaly, abnormal tone, and profound psychomotor delay combined with typical findings on CT scan or magnetic resonance imaging (MRI) of the brain. Neuronal degeneration (6) and maturational defects (7) in the pons, cerebellum and other brain stem nuclei may play a role in the pathogenesis of PCH. Subtype grouping of PCH based on clinical criteria is difficult. To date, six types of PCH (OMIM# 607596, 277470, 608027, 225753, 610204 and 611523) have been described based on various clinical and genetic criteria (8–10). We report the genetic etiology of PCH in two children from a consanguineous family (Figure S1, supporting information online) of Middle Eastern descent with symptoms that were not completely consistent with any of the previously described PCH types. The two patients were delivered spontaneously at term. At birth, they were found to have hypokinesis, tremulousness, hypertonia, increased upper extremity tone with tight flexion of arms, dysfunctional oral motor skills, mild retrognathia, and no obvious dysmorphism. Metabolic workup was normal. Isoelectric focusing of serum transferrin excluded congenital disorders of glycosylation. Brainstem evoked response was normal. Optic atrophy was absent. Brain CT scan and MRI showed hypoplasia of the pons and the cerebellum (11). Their anthropometric measurements stagnate at more than two standard deviations below normal in the fifth year for the older child and sixth month in the younger. Questionable visual fixation, brisk reflexes, positive Babinski, intermittent seizures and lower limb scissoring were observed in the first child. Both children suffer from profound global developmental delay. Extrapyramidal symptoms such as chorea and dystonia were yet to be appreciated in either of the two children at the ages of 4 and 1, respectively (11). Table 1 shows a summary of their clinical features. The parents of the affected children are first cousins making it probable that the disease causing allele is homozygous by descent in the affected children. We tested for homozygosity of singlenucleotide polymorphisms (SNPs) derived from candidate loci (Table S1, supporting information online), and were able to rule out three out of five causative loci; chr 7q11-21, RARS, and TSEN34, which are linked, respectively, to PCH type 3, 6, and 2 (9, 10, 12). We sequenced all exons and exon–intron junctions of TSEN2 because we found no heterozygous SNPs. This sequence was identical to the reference sequence in all members of the family. However, SNPs in the region of TSEN54 (linked to PCH type 2 and 4) showed homozygosity in the affected children, while the parents and unaffected children were heterozygous. To determine if these children harboured a mutation in TSEN54 we performed direct DNA sequence analysis of all 11 exons and the exon–intron junctions. A single point mutation, c.919G > T in exon 8 was identified. Both affected children were homozygous, while the healthy family members were heterozygous for the mutation (Fig. 1a). A diagnostic assay with