From time to time we have observed children and young adults with unmistakable progressive spastic paraplegia superimposed on a sensorimotor polyneuropathy of extremely chronic evolution. Sural nerve biopsy in 2 of our cases disclosed a typical “hypertrophic” polyneuropathy. In another case, only loss of nerve fibers was found. Cavanaugh and colleagues and Harding and Thomas (1984) reported similar patients. Our patients were severely disabled, being barely able to stand on their atrophic legs. An even more ambiguous form of disease was described by Vucic and colleagues in which there is typical CMT but with brisk reflexes. There were Babinski signs in half the patients and spastic dysphonia in a few others. The mutation is not known.
Although few in number, some cases of chronic polyneuropathy are combined with optic atrophy, with or without deafness or retinitis pigmentosa, and Dyck and Lambert (1975) classed these in a separate group. Jaradeh and Dyck have also described a hereditary motor-sensory polyneuropathy with the later development of a parkinsonian or a choreic-dystonic syndrome that responded to l-dopa. Most cases of this type have had an autosomal recessive inheritance.
This entity, mentioned earlier in relation to hereditary neuropathy with pressure palsies because of the implication of a similar genetic locus, is discussed in the later section under “Brachial Neuritis, Brachial Plexitis (Neuralgic Amyotrophy, Parsonage-Turner Syndrome).”
Refsum Disease (HMSN IV, PHYH, and PEX7 Mutations)
This rare disorder, named after Refsum who made the first clinical observations, is inherited as an autosomal recessive trait and has its onset in late childhood, adolescence, or early adult life. It is slowly progressive but may be punctuated by acute or subacute worsening. Clinical diagnosis is based on a combination of clinical manifestations—retinitis pigmentosa, ataxia, and chronic polyneuropathy—coupled with the metabolic marker of the disease, an increase in blood phytanic acid. Phytanic acid accumulates because of a deficiency of the peroxisomal enzyme, phytanoyl-coenzyme A (CoA) hydroxylase. The deficiency is caused by mutations in 1 of 2 disparate genes. Cardiomyopathy and neurogenic deafness are present in most patients, and pupillary abnormalities, cataracts, and ichthyotic skin changes (particularly on the shins) are added features in some. Anosmia and night-blindness (nyctalopia) with constriction of the visual fields may precede the neuropathy by many years. The polyneuropathy is sensorimotor, distal, and symmetrical in distribution, affecting the legs more than the arms. All forms of sensation are reduced, often deep sensation more so than pain and thermal sense, and tendon reflexes are lost. The CSF protein is increased, sometimes markedly. Usually, the polyneuropathy develops gradually, although in some patients it has a subacute onset or, after being established for some time, a tendency to worsen fairly abruptly.
Although the nerves may not be palpably enlarged, “hypertrophic” changes with onion-bulb formation are invariable pathologic features. The metabolic defect has been discovered to be in the utilization of dietary phytol; a failure of oxidation of phytanic acid—a branched-chain tetramethylated 16-carbon fatty acid—that accumulates in the absence of activity of the enzyme phytanoyl-CoA-hydroxylase. The relation between the increased phytanic acid and the polyneuropathy is uncertain.