Congenital Arthrogryposis With Anterior Horn Cell Disease

A number sign (#) is used with this entry because of evidence that congenital arthrogryposis with anterior horn cell disease (CAAHD) is caused by homozygous or compound heterozygous mutation in the GLE1 gene (603371) on chromosome 9q34.

Lethal congenital contracture syndrome-1 (LCCS1; 253310) is also caused by biallelic mutation in the GLE1 gene.

Description

Congenital arthrogryposis with anterior horn cell disease (CAAHD) is an autosomal recessive neuromuscular disorder with highly variable severity. Affected individuals are usually noted to have contractures in utero on prenatal ultrasound studies, and present at birth with generalized contractures manifest as arthrogryposis multiplex congenita (AMC). Patients have severe hypotonia with respiratory insufficiency, often resulting in death in infancy or early childhood. Some patients may survive into later childhood with supportive care, but may be unable to walk or sit independently due to a combination of muscle weakness and contractures. Cognition may be normal. The disorder also includes multiple congenital anomalies associated with AMC and hypotonia, including high-arched palate, myopathic facies, and bulbar weakness. Neuropathologic studies demonstrate severe loss of anterior horn cells in the spinal cord, as well as diffuse motor neuron axonopathy (summary by Smith et al., 2017 and Tan et al., 2017).

Distinction from Lethal Congenital Contracture Syndrome 1

Biallelic mutation in the GLE1 gene can also cause LCCS1, which is lethal in utero. However, distinguishing between LCCS1 and CAAHD is controversial. Smith et al. (2017) suggested that differentiating between the 2 disorders has limited utility, and that they may represent a genotype/phenotype correlation rather than 2 different disease entities. In contrast, Said et al. (2017) concluded that LCCS1 represents a distinct clinical entity in which all affected individuals die prenatally and exhibit no fetal movements.

Vuopala et al. (1995) differentiated CAAHD from LCCS1, noting that both are prevalent in Finland. LCCS1 is always fatal during the fetal period, presenting with severe hydrops and intrauterine growth retardation. In LCCS1, the spinal cord is macroscopically thinned because of an early reduction of the anterior horn and a paucity of anterior horn cells. The skeletal muscles are extremely hypoplastic, even difficult to locate. Infants with CAAHD survive longer than those with LCCS1, and when present, hydrops and intrauterine growth retardation are mild. The macroscopic findings of the central nervous system and skeletal muscles are closer to normal, although microscopic analysis also shows degeneration of anterior horn cells. In addition, birthplaces of ancestors of affected individuals do not show clustering in the northeast part of Finland, as is the case with LCCS1.

Clinical Features

Vuopala et al. (1995) described 15 infants from 11 Finnish families with a phenotype of lethal arthrogryposis and anterior horn motor neuron loss. The clinical presentation was the fetal akinesia deformation sequence (FADS) with multiple contractures and facial anomalies. The phenotype was uniform with low-set ears, hypoplastic jaw, short neck, and contractures. Malpositions in the extremities were moderate, distal, and inwardly spiral. The mean gestational age was 34 weeks, with 8 infants being born at term. Most of the cases were perinatal lethal; 3 infants were stillborn, 5 died within 1 hour, 6 died within a few days, and 1 survived for 20 days. Skeletal muscles were affected in all infants, but the severity of pathologic findings varied. A tibialis muscle sample from one infant showed severe neurogenic atrophy with normally shaped muscle spindles and normal number and differentiation of intrafusal fibers. The size and shape of the spinal cord at different levels were normal, but the anterior horn motor neurons were degenerated and diminished in number. The families came from different parts of Finland, and no geographic clustering was observed.

Smith et al. (2017) reported 2 sibs, born of unrelated parents of European descent, with CAAHD. Both were born with multiple congenital contractures, rocker-bottom feet, and severe hypotonia with respiratory insufficiency necessitating ventilation. One sib died at 14 days of age due to respiratory insufficiency, whereas the other was still alive at 12 years of age. The deceased sib presented at birth with low-set ears, ptosis, high-arched palate, retrognathia, and undescended testes. Postmortem examination showed severe loss of anterior horn cells in the spinal cord. The living sib required tube feeding and tracheostomy from 4 months of age. At age 12, he had global developmental delay and was nonverbal, but able to communicate by keyboard or sign language. He was unable to stand, but showed gradual improvement in muscle strength and was able to sit with support. Other features included microcephaly, myopia, facial diplegia, high-arched palate, kyphoscoliosis, dysplastic hips, rocker-bottom feet, and prominent bulbar weakness. He had brisk reflexes in the upper limbs, but absent knee and ankle reflexes, as well as decreased muscle bulk and paucity of muscle fibers on biopsy. Electrophysiologic studies showed a diffuse motor axonopathy with a neurogenic component. Brain imaging showed diffuse cerebral atrophy and dilated ventricles, and EEG showed focal discharges associated with clinical seizures that were controlled by medication. Smith et al. (2017) noted that the phenotype in these patients, particularly the 12-year-old sib, represented an appreciable expansion of the phenotype associated with biallelic GLE1 mutations.

Said et al. (2017) reported 2 unrelated children, each born of unrelated non-Finnish parents, with a protracted form of CAAHD. One patient (family A) was a 5-year-old boy who presented with severe respiratory distress necessitating ventilation soon after birth. He had dysmorphic features, including prominent forehead, downslanting palpebral fissures, tent-shaped mouth, micrognathia, low-set ears, and congenital contractures with clubfeet. He was hypertonic with jerky movements. He showed delayed motor development and markedly decreased muscle bulk, but was able to walk with an unsteady gait by 4 years of age. He had poor expressive speech due to micrognathia, but receptive language was normal. The other patient (family B) presented at 12 months of age with delayed development and was able to stand at 15 months. She also had poor speech and dystonic and involuntary movements. She later developed recurrent infections that exacerbated the neurologic symptoms and resulted in loss of gross motor skills. Brain imaging in this patient showed generalized volume loss and a small brainstem. She died of a respiratory infection at age 4.

Tan et al. (2017) reported a girl, born of unrelated parents of Caucasian descent, with CAAHD. She was born prematurely at 36 weeks' gestation and showed contractures, hypotonia, and respiratory insufficiency. She eventually needed a feeding tube and tracheostomy due to muscle weakness. Additional features included prominent forehead, depressed nasal bridge, low-set ears, and excess nuchal folds. She had clenched fists, ulnar deviation of her fingers, single palmar crease on her right hand, and talipes equinovarus. She had slow but persistent motor, cognitive, and language development, although she was only able to pull herself to standing by age 2 years. Skeletal muscle biopsy showed denervation, consistent with anterior horn cell disease.

Paakkola et al. (2018) reported 2 sibs, born of consanguineous parents from northeastern Finland, with CAAHD resulting in death in infancy. Although prenatal ultrasound was essentially normal in both, they presented at birth with arthrogryposis, hypotonia, decreased muscle mass, and areflexia. They had progressive respiratory insufficiency and feeding difficulties necessitating tube feeding and tracheostomy. Additional features included myopathic facies, small jaw and mouth, ptosis, and weak cry. Both had slowing of background activity on EEG; 1 had epileptiform discharges. Muscle biopsy showed neurogenic atrophy, and postmortem examination of the spinal cord showed loss of anterior horn motor neurons.

Inheritance

The transmission pattern of CAAHD in the families reported by Smith et al. (2017) and Said et al. (2017) was consistent with autosomal recessive inheritance.

Molecular Genetics

To investigate whether LCCS1 and CAAHD represent allelic disorders, Nousiainen et al. (2008) screened 9 unrelated families with CAAHD for mutations in the GLE1 gene and identified 12 individuals with mutations. All 12 patients had compound heterozygous mutations: 6 were heterozygous for the LCCS1 major Finnish mutation (Fin(Major); 603371.0001) and a missense point mutation in exon 13 (603371.0003), and the remaining 6 carried the Fin(Major) mutation and a missense mutation in exon 16 (603371.0004). The authors investigated an additional patient who had been diagnosed initially with severe infantile spinal muscular atrophy (see 253300) but carried no SMN gene deletion. This patient was also compound heterozygous for Fin(Major) and the exon 16 missense mutation. Autopsy revealed typical neurogenic muscular atrophy and loss of anterior horn cells of the spinal cord. Nousiainen et al. (2008) concluded that homozygosity for the Fin(Major) mutation results in a more severe phenotype (LCCS1) than does compound heterozygosity.

In 2 brothers, born of unrelated non-Finnish parents, with CAAHD, Smith et al. (2017) identified compound heterozygous splicing mutations in the GLE1 gene (603371.0005 and 603371.0006). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Analysis of patient cells showed that 1 transcript was detected, whereas the other was only weakly expressed, likely due to nonsense-mediated mRNA decay. However, the wildtype transcript was also present at low levels, which Smith et al. (2017) suggested may explain the postnatal survival of these patients.

In 2 unrelated patients, each born of unrelated non-Finnish parents, with CAAHD, Said et al. (2017) identified homozygous or compound heterozygous missense mutations at conserved residues in the GLE1 gene (S693F, 603371.0007; R569H, 603371.0002; and R584W, 603371.0008). The mutations were found by exome sequencing. Functional studies of the variants and studies of patient cells were not performed, but the mutations occurred at highly conserved residues outside of the coiled-coil domain. Said et al. (2017) suggested that patients with mutations occurring outside of the coiled-coil domain, which is necessary for oligomerization of GLE1, may have a less severe phenotype with survival beyond the perinatal period compared to patients with mutations that disrupt the coiled-coil domain (see, e.g., 603371.0001) who have the more severe disorder LCCS1 that is lethal in utero.

In a girl with CAAHD, Tan et al. (2017) identified compound heterozygous missense mutations in the GLE1 gene (R603L and G666V), both of which occurred outside of the coiled-coil domain. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variants were not performed.

In 2 sibs, born of consanguineous parents from northeastern Finland, with CAAHD, Paakkola et al. (2018) identified a homozygous missense mutation in the GLE1 gene (I684T; 603371.0004). The mutation, which was found by a combination of homozygosity mapping and exome sequencing, segregated with the disorder in the family. Patient fibroblasts showed decreased nuclear levels of GLE1 protein compared to controls.

Genotype/Phenotype Correlations

Paakkola et al. (2018) concluded that there is a specific genotype/phenotype correlation associated with biallelic GLE1 mutations. Those who are homozygous for the Finn(Major) mutation (603371.0001), which disrupts the coiled-coil domain (Nousiainen et al., 2008) have LCCS1 with absent fetal movements and death in utero. Those with missense mutations in other regions of the gene, even if in compound heterozygosity with the Finn(Major) variant, usually survive the perinatal period, although many die in infancy or early childhood.