Congenital hypomyelinating neuropathy, a long term follow-up study in an affected family

1. Introduction 

Congenital hypomyelinating neuropathy (CHN) is a rare condition characterized by prenatal, neonatal or early infantile onset of hypotonia, predominantly distal weakness, areflexia and very slow motor nerve conduction velocities. Swallowing and respiratory difficulties are usually present. The few patients described in literature with a severe neonatal form accompanied by arthrogryposis multiplex congenita died within the first years of life. Death usually occurs due to complications of respiratory infections [1], [2], [3].

Histopathologically, peripheral nerves show absent or thin myelin sheaths, suggesting an intrinsic defect of myelin synthesis. Arrest of peripheral myelination at the promyelin stage appears to be the origin of myelin deficiency [1].

There is some debate that this condition is within the spectrum of the Dejerine–Sottas syndrome (DSS) [2], [3], [4]. It is also argued that CHN has distinct entities with unique clinical and pathological features for a disorder of myelin formation, and not for a demyelinating disorder.

Several genes causing CHN, like EGR2, MPZ, PMP22 and others have been described in the literature. Here we present 2 cases within one family, a newborn girl, our index patient, and her 27-year-old father with a heterozygous mutation in MPZ. To our knowledge, this is the first confirmed family case in two generations, and the only reported adult with CHN.

2. Case report 

The index patient, a one-day-old girl, was born at a gestational age of 34 weeks, after a very eventful pregnancy. In the 28th week of pregnancy a hydrothorax was diagnosed and thoracic–amniotic shunts were intrauterinely placed. During the ultrasounds hypokinesia was observed. After a spontaneous delivery the Apgar-scores were 1, 1 and 3 after 1, 5 and 10min, respectively. She required resuscitation and subsequent assisted ventilation. Physical examination showed hypokinesia, hypotonia, areflexia and arthrogryposis of both hands and feet.

Nerve conduction studies, 10 days after birth, showed a severe demyelinating polyneuropathy. Compound motor action potentials (CMAP) of the median nerve was 3.3mV and motor nerve conduction showed severe slowing (4m/s; normal value: mean 26, SD 2.2m/s [5]). Peroneal and tibial nerve examination did not reveal motor action potentials, sensory studies were not performed.

She needed respiratory support until 3 months of age and had several aspiration pneumonias.

The family history learned that the father was extensively known to our hospital. He was born at term in 1977 after an uneventful pregnancy. The Apgar-scores were 3 and 6 after 1 and 5min, respectively, with spontaneous recovery. The neonatal period was complicated by swallowing difficulties, pneumonia, hyper-extensive posturing and hypotonia. Nerve conduction studies were not performed. At that time, it was concluded that he probably had a hypoxic–ischemic encephalopathy caused by perinatal asphyxia. He had delayed motor milestones, but was able to walk with aid from the age of 4 years. His clinical condition was not progressive. Partly wheelchair bound, he is working in administration. He and his wife are not consanguineous. Family history is otherwise unremarkable.

At present, neurological examination reveals distal weakness and sensory disturbances, areflexia and no signs of central nervous system involvement. He has contractures of the distal lower extremities and a severe thoracic scoliosis. EMG showed no motor responses except for the median nerve with a distal CMAP of 0.8mV, and a single fiber pattern at needle examination. MRI of the brain showed no abnormalities.

Since father and daughter seemed to have the same condition, the father underwent a sural nerve biopsy. This revealed the absence of myelin sheaths on light microscopy. Electron microscopy showed no myelinated fibers, with the exception of a single fiber with a very thin layer of myelin. There was no clear classic onion bulb formation and there were no signs of inflammation, consistent with the diagnosis of congenital hypomyelinating neuropathy (Fig. 1).

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Fig. 1. Electron microscopic study of nerve biopsy of patient 2, the father: Schwann cell structures with one or more unmyelinated fibers (→). No myelinated fibers present (2800×).

Both father and daughter were tested for mutations in demyelinating neuropathy associated genes (i.e., PMP22 duplication and sequence alterations in PMP22, MPZ, EGR2, GJB1, LITAF, MTMR2 and a SNP in CNTF (rs1800169)) and were both found to be heterozygous for an insertion of a G nucleotide in exon 4 of the MPZ gene (NM_000539:c.549–550InsG, p.Leu184AlafsX51).

3. Discussion 

Our index patient was diagnosed with congenital hypomyelinating neuropathy, as was her father at the age of 27 years. To our knowledge, this is the oldest living patient and the only confirmed family case in two generations, described in literature.

Both father and daughter presented with neonatal hypotonia, hypokinesia and areflexia. Swallowing and respiratory difficulties were present. Our index patient also had arthrogryposis, and extremely slow nerve conduction velocities, consistent with the diagnosis of hypo- or demyelinating neuropathy.

CHN and Dejerine–Sottas syndrome (DSS) are both congenital neuropathies with neonatal onset. It has been argued that these are distinct entities with unique clinical and pathological features [2], [3]. In CHN, hypo- or amyelination is found in most or in all fibers with lack of inflammation. In DSS enlarged nerves with classic onion bulbs and evidence for demyelination–remyelination suggestive of myelin breakdown are found. Others have suggested that CHN is a subgroup of DSS or that evidence for myelin breakdown becomes more evident in time in the DSS/CHN-spectrum [2]. The sural nerve biopsy of the father, however, did not show clear signs of classic onion bulb formation or signs of myelin breakdown.

In both DSS and CHN, mutations in MPZ, EGR2, PMP22 and MTMR2 are found. Myelin protein zero (MPZ) is a transmembrane protein of the immunoglobulin family. It is one of the major myelin structural protein in the peripheral nervous system, expressed by myelinating Schwann cells [6], [7]. It contains a large glycosylated immunoglobulin-like extracellular domain which gives adhesion properties to the protein, and a smaller basic intracellular domain that participates in electrostatic interactions [8]. Mutation in MPZ gene are also found in Charcot–Marie-Tooth disease type 1B (CMT1B), type 2 (CMT2), and Roussy–Levy syndrome [8], [9], [10]. These diseases or syndromes have a less severe phenotype and a different clinical and neuropathological profile than CHN [10]. In general, there are two distinct phenotypes in patients with MPZ mutations: (1) an early (infantile) onset disease with very slow nerve conductions, with abnormalities of myelin as the prominent features in nerve biopsies and (2) a late (adult) onset disease with only minimally to moderately slow nerve conductions, with more axonal degeneration and less demyelination. It has been hypothesized that the location and type of mutation within MPZ may determine the clinical phenotype [8]. Shy et al., however did not find a consistent correlation of the location with the phenotype [11].

From the genetic tests, we conclude that both father and daughter are heterozygous for the c.549–550InsG. This frameshift mutation results in loss of the protein kinase C target motif (RSTK), which is important for adhesion of MPZ. MPZ forms dimers and tetramers in intact myelin [8], [12]. We did not find this mutation in 900 control chromosomes. In literature only three other MPZ mutations, responsible for CHN, are described (Table 1). Heterozygosity for a mutant MPZ allele may compromise dimerization and tetramerization. Functional studies of MPZ show that mutations in the intracellular domain that interrupt the RSTK motif, abolish MPZ-mediated adhesion and thereby also influence the myelination process [13]. Therefore, we conclude that this mutation is responsible for the hypomyelination described in both patients. We have no explanation for the difference in severity between father and daughter. Since severely affected patients can carry mutations in two CMT genes we searched for sequence alterations in PMP22, LITAF, GJB1, EGR2, MTMR2 and CNTF [14]. No mutations were found in the coding region of these genes, thus digenism for mutations in these CMT1 genes in the daughter is unlikely so far. However, we cannot exclude that other genes contribute to the variability of the phenotype.

Table 1. Mutations in MPZ with a clinical phenotype of CHN

		Mutation	Alias	Phenotype	Citations
	1	c.371C>A	p.Thr124Lys Extracellular, dominant negative effect, ∼7 years of age	CHN	Kochanski et al. [15]
	2	c.550_552delCTAinsG	p.Leu184fs Cytoplasmic disturbance of the MPZ mediated adhesion, <6 months of age	CHN + cranial nerve dysfunction + respiratory failure + hypertrophic cardiomyopathy	Szigeti et al. [9]
	3	c.643C>T	p.Gln215stop Cytoplasmic, 12 months (∼?7yrs)	CHN	Warner et al. [8]; Mandich et al. [10]
	4	c.549–550InsG	p.Leu184AlafsX51 Cytoplasmic early onset	CHN	Smit et al. (present study)

The neonatal form of CHN often leads to death due to infections. Of the 11 patients with a neonatal onset of CHN previously described, six patients died before the age of 7 years. The other five patients were followed until the age of 6–17 years [2], [15]. Generally, patients with a presentation later in infancy seemed to have a better prognosis. Some of these patients could learn to walk with support by 4 years of age. others however died before the age of four.

In one described family three siblings are affected with CHN [16]. No other confirmed families with two generations affected by CHN have been reported.

There are a few reports of family cases, but either it was difficult to classify the clinical profile or the diagnosis was not confirmed or consistent with neuropathological investigation [17], [18], [19].

In conclusion, we report a two generation familiar case of confirmed CHN, including the oldest described patient in literature, both having a heterozygous mutation in the MPZ-gene.