Neuropathy, Congenital Hypomyelinating, 3
A number sign (#) is used with this entry because of evidence that congenital hypomyelinating neuropathy-3 (CHN3) is caused by homozygous or compound heterozygous mutation in the CNTNAP1 gene (602346) on chromosome 17q21.
Biallelic mutation in the CNTNAP1 gene can also cause lethal congenital contracture syndrome-7 (LCCS7; 616286), a similar disorder with more prominent congenital contractures. CHN3 and LCCS7 represent a phenotypic spectrum resulting from mutations in the CNTNAP1 gene.
DescriptionCongenital hypomyelinating neuropathy-3 is an autosomal recessive neurologic disorder characterized by onset of neurogenic muscle impairment in utero. Affected individuals present at birth with severe hypotonia, often causing respiratory insufficiency or failure and inability to swallow or feed properly. They have profoundly impaired psychomotor development and may die in infancy or early childhood. Those that survive are unable to sit or walk. Sural nerve biopsy shows hypomyelination of the nerve fibers, and brain imaging often shows impaired myelination and cerebral and cerebellar atrophy. Nerve conduction velocities are severely decreased (about 10 m/s) or absent due to improper myelination (summary by Vallat et al., 2016 and Low et al., 2018).
For a discussion of genetic heterogeneity of CHN, see CHN1 (605253).
Clinical FeaturesVallat et al. (2016) reported 2 sets of brothers from 2 unrelated nonconsanguineous families with CHN3. These families were subsequently reported as a French family by Nizon et al. (2017) (family 2 in Vallat et al., 2016), and a northern Irish family by Hengel et al. (2017) (family 2 in Hengel et al., 2017 and family 1 in Vallat et al., 2016). The patients presented at birth with severe hypotonia, poor or absent independent respiration and swallowing, absent or rare voluntary movements, and areflexia. All died within the first hours or months of life. Some of the pregnancies were complicated by oligohydramnios and reduced fetal movements. Dysmorphic features included clubfoot, micrognathia, facial diplegia, ptosis, dolichocephaly, epicanthal folds, thick nares and lips, narrow palate, and gingival hypertrophy. No arthrogryposis was noted in these patients. One of the patients (Hengel et al., 2017) developed seizures at age 10 weeks. Nerve conduction velocities (NCV) of 1 patient showed severely decreased motor NCV (about 10 m/s) and absent sensory nerve action potentials. EMG findings were consistent with early muscle denervation. Sural nerve biopsies showed significantly decreased myelinated fibers or fibers with thin myelin sheaths (hypomyelination). Electron microscopy showed that several myelinated fibers were surrounded by proliferations of the basal laminae, similar to onion bulbs, as well as marked widening of the nodes of Ranvier, absence of transverse bands of the myelin loop with loss of contact between myelin and the axolemma, and a loss of attachment between the axon and the paranodal loops. Brain imaging, when performed, showed poor early myelination.
Hengel et al. (2017) reported 3 patients from a multigenerational, highly consanguineous Israeli family of Palestinian descent with CHN3. Two first cousins, aged 9 and 12 years, were found to have multiple congenital anomalies affecting the skeleton and brain on fetal ultrasound. The pregnancies were also complicated by polyhydramnios. Both children were diagnosed with arthrogryposis multiplex congenita (AMC) at birth, with clenched hands, contractures of the elbows, knees, and feet. They had profound hypotonia and hypoventilation, necessitating ventilatory support, absent swallow with facial diplegia, and severe developmental disabilities with inability to sit, walk, or talk, as well as severe intellectual disability, absent eye contact, and no response to sound stimuli. Dysmorphic features included microcephaly, low-set ears, cleft palate, and micrognathia. Both later developed generalized epilepsy with tonic-clonic seizures and hyperreflexia with positive Babinski sign. They received nutrition by gastrostomy and underwent tracheostomy. Brain imaging of 1 patient showed severe hypomyelinating leukodystrophy with no signs of myelination even in parts of the brain, reduced cerebral, cerebellar, and pontine volume, thin corpus callosum, and mega cisterna magna. Further follow-up of the family revealed a 4-week-old child in a distantly related family branch who had a history of polyhydramnios, similar dysmorphic features, and hypotonia; however, this patient had no joint contractures or signs of AMC. The findings indicated that contractures can be a variable manifestation of the disorder, even within the same family.
Mehta et al. (2017) reported a patient with CHN3 who died at 1 month of age. He presented at birth without respiratory effort, minimal spontaneous movements, and absent primitive reflexes. He had clubfeet, flexion posture with ulnar deviation of the wrists, undescended testes, and absent peripheral reflexes. The patient did not have frank AMC, but some of his features were suggestive of contractures. EMG and sural nerve biopsy indicated a neurogenic process with decreased median motor nerve conduction velocity (25 m/s), decreased or absent CMAPs, abundant fibrillation potentials, a reduction in large myelinated fibers, and hypomyelination.
Low et al. (2018) reported 7 children, including 2 sibs, between 3 months and 15 years of age, with CHN3. Only one of the patients died, at 3 months of age. Most of the pregnancies were complicated by polyhydramnios and premature delivery. All patients had profound global developmental delay, central and peripheral hypotonia, orobulbar dysfunction with poor breathing and swallowing, high-arched palate, and myopathic facies. Most, but not all, had joint contractures. Additional common findings included scoliosis, gum hyperplasia, visual impairment, and hearing loss. Brain imaging showed central hypomyelination/demyelination, variably reduced white matter volume, and cerebral atrophy. Sural nerve biopsies showed thinly myelinated fibers and severe hypomyelination. Low et al. (2018) emphasized that their findings showed that the disorder is not always lethal in infancy and that survival into childhood can occur.
InheritanceThe transmission pattern of CHN3 in the families reported by Vallat et al. (2016) was consistent with autosomal recessive inheritance.
Molecular GeneticsIn 2 sets of brothers from 2 unrelated families with CHN3, Vallat et al. (2016) identified compound heterozygous mutations in the CNTNAP1 gene (602346.0004-602346.0007). These families were later reported by Hengel et al. (2017) and Nizon et al. (2017). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Functional studies of the variants and studies of patient cells were not performed, but the mutations were predicted to result in a loss of function.
By whole-exome sequencing, Mehta et al. (2017) identified a homozygous missense mutation in the CNTNAP1 gene (R388P; 602346.0008) in a patient with lethal CHN3. In vitro functional studies of the variant were not performed.
In 7 patients, including 2 sibs, with CHN3, Low et al. (2018) identified homozygous or compound heterozygous mutations in the CNTNAP1 gene (see, e.g., 602346.0009 and 602346.0010). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The mutations included 3 missense, 4 nonsense, 1 frameshift, and 1 splice site. All of the missense mutations occurred at conserved structural or functional domains and were predicted to adversely affect protein function according to ACMG guidelines, consistent with a loss of function. In vitro functional studies of the variants and studies of patient cells were not performed.
Genotype/Phenotype CorrelationsLow et al. (2018) hypothesized that CHN3 patients with homozygous nonsense or frameshift mutations in the CNTNAP1 gene may have a more severe disorder with early lethality and neonatal respiratory failure compared to those who have one or more missense alleles, suggesting that the missense alleles may be hypomorphic and confer some residual function. There was no apparent molecular mechanism to account for the presence or absence of AMC, which may have more to do with diagnostic labeling.