Pelizaeus-Merzbacher-like disease type 1 (PMLD1), a slowly progressive leukodystrophy, typically begins in neonatal period or early infancy. PMLD1 manifests with nystagmus, commonly associated with hypotonia, delayed acquisition of motor milestones, speech delay, and dysarthria. Over time, hypotonia reverts into spasticity, which affects the ability to walk and to communicate. Cerebellar signs (i.e. gait ataxia, dysmetria, intention tremor, head titubation, dysdiadochokinesia) frequently manifest during childhood. Brain MRI shows characteristic signal abnormalities consistent with cerebral hypomyelination. Cerebellar white matter might also be involved albeit signal changes appear often less severe. Some patients develop extrapyramidal movement abnormalities like choreoathetosis and dystonia. In rare cases, hearing loss and optic atrophy are observed. Motor impairments can lead to difficulties swallowing as well as orthopaedic complications, including hip dislocation and scoliosis. Most individuals have normal cognitive abilities or mild intellectual disability.
The clinical features overlap with the one in Pelizaeus-Merzbacher disease (PMD) and are caused by mutations in PLP1, which encodes proteolipoprotein 1, the major protein of CNS myelin. Epilepsy is more frequent in PMLD. In addition, PMLD shows more prominent brain stem involvement on MRI.
Hereditary spastic paraplegia 44 (SPG44) is a hypomyelinating leukodystrophy. A recessive mutation (p.Ile33Met) has been associated with SPG44. The phenotype is less severe than PMLD. SPG44 is characterized by a late-onset, slowly progressive spastic paraplegia associated with mild ataxia and dysarthria, upper extremity involvement, preserved walking capability through adulthood, and mild cognitive impairment, without the presence of nystagmus. In all cases, a thin corpus callosum is observed, and psychomotor development is normal or near normal. Orthmann-Murphy et al., 2009 reported on three members of a large Italian family. Although mild symptoms were reported in the first or second decade, a more severe course with disability occurred in the third decade.
Hereditary lymphedema type 1C (LMPH1C) with autosomal dominant inheritance is caused by anatomic or functional defects in the lymphatic system, resulting in chronic swelling of body parts. There may be accompanying nail and skin changes, such as nail dysplasia or papillomatosis. The disease with variable severity usually begins at birth or in early childhood, but can also occur later.
GJC2