Expanded spectrum of Pelizaeus–Merzbacher-like disease: literature revision and description of a novel GJC2 mutation in an unusually severe form

Abstract

Homozygous or compound heterozygous mutations in the GJC2 gene, encoding the gap junction protein connexin47 (Cx47), cause the autosomal recessive hypomyelinating Pelizaeus-Merzbacher-like disease (PMLD1, MIM# 608804). Although clinical and neuroradiological findings resemble those of the classic Pelizaeus-Merzbacher disease, PMLD patients usually show a greater level of cognitive and motor functions. Unpredictably a homozygous missense GJC2 mutation (p.Glu260Lys) was found in a patient presenting with a very severe clinical picture characterised by congenital nystagmus and severe neurological impairment. Also magnetic resonance imaging was unusually severe, showing an abnormal supra-and infratentorial white matter involvement extending to the spinal cord. The novel p.Glu260Lys (c.778G4A) mutation, occurring in a highly conserved motif (SRPTEK) of the Cx47 extracellular loop-2 domain, was predicted, by modelling analysis, to break a 'salt bridge network', crucial for a proper connexin-connexin interaction to form a connexon, thus hampering the correct formation of the connexon pore. The same structural analysis, extended to the previously reported missense mutations, predicted that most changes were expected to have less severe impact on protein functions, correlating with the mild PMLD1 form of the patients. Our study expands the spectrum of PMLD1 and provides evidence that the extremely severe clinical and neuroradiological PMLD1 form of our patient likely correlates with the predicted impairment of gap junction channel assembly resulting from the detrimental effect of the new p.Glu260Lys mutant allele on Cx47 protein.

Hypomyelinating Leukodystrophy due to HSPD1 Mutations: A New Patient

“…1 Diffusion restriction within the pyramidal tract is not common in PMD or PMLD, but recently it was reported in a patient with a missense mutation in GJC2 and severe hypomyelination. 15 It may be consistent with intramyelinic edema and could be a characteristic of patients with hypomyelination not caused by PLP1 mutations.…”

GJC2 promoter mutations causing Pelizaeus–Merzbacher-like disease

“…[14] Patients with c.-167A>G mutations achieved walking with support (three cases) or autonomous walking (13 cases). [3, 5, 12, 13] though in most cases independent ambulation was ultimately lost.…”

“…Published PMLD patients with promoter region mutations appear to have a milder course than PMLD overall[14] with the greatest majority achieving independent ambulation, and all achieving at least supported walking, though this is typically later lost. There are currently too few patients, however, to know whether there is a correlation between promoter region mutations and a milder disease course and this requires further study.…”

“…Existing literature was reviewed for cases of GJC2 promoter region mutations, and where clinical data was sufficient, cases were scored according to the motor function score previously used in the PMD and PMLD patient groups[1, 14]. …”

Mutations in cardiovascular connexin genes

“…These patients are suffering from Pelizaeus–Merzbacher‐like disease (PMLD). PMLD has been linked to a mutation in HSPD1 (Magen et al., ), to various autosomal recessive mutations in GJC2 and to several mutations in the GJC2 promoter (Table and Figure ; Orthmann‐Murphy et al., ; Henneke et al., ; Al‐Yahyaee et al., ; Yalcinkaya et al., ; Biancheri et al., ; Kammoun Jellouli et al., ; Shimojima et al., ). In addition, mutations in GJC2 are linked to hereditary spastic paraplegia; a milder but similar phenotype (Orthmann‐Murphy et al., ).…”