Inborn Errors of Metabolism: Refsum Disease.

Patient with Refsum disease present with nyctalopia, and the fundus shows progressive panretinal degeneration. Vision gradually decreases, with progressive peripheral constriction. The pupil usually does not dilate well.

HMSN Lom in 12 Czech patients, with one unusual case due to uniparental isodisomy of chromosome 8.

Hereditary motor and sensory neuropathy-type Lom (HMSNL), also known as CMT4D, a demyelinating neuropathy with late-onset deafness is an autosomal recessive disorder threatening Roma population worldwide. The clinical phenotype was reported in several case reports before the gene discovery. HMSNL is caused by a homozygous founder mutation p.Arg148* in the N-Myc downstream-regulated gene 1. Here, we report findings from the Czech Republic, where HMSNL was found in 12 Czech patients from eight families. In these 12 patients, 11 of the causes were due to p.Arg148* mutation inherited from both parents by the autosomal recessive mechanism. But in one case, the recessive mutation was inherited only from one parent (father) and unmasked owing to an uniparental isodisomy of the entire chromosome eight. The inherited peripheral neuropathy owing to an isodisomy of the whole chromosome pointed to an interesting, less frequent possibility of recessive disease and complications with genetic counseling.

Marked inhibition of Na+, K(+)- ATPase activity and the respiratory chain by phytanic acid in cerebellum from young rats: possible underlying mechanisms of cerebellar ataxia in Refsum disease.

Refsum disease is an autosomal recessive disorder of peroxisomal metabolism biochemically characterized by highly elevated concentrations of phytanic acid (Phyt) in a variety of tissues including the cerebellum. Reduction of plasma Phyt levels by dietary restriction intake ameliorates ataxia, a common clinical manifestation of this disorder, suggesting a neurotoxic role for this branched-chain fatty acid. Therefore, considering that the underlying mechanisms of cerebellum damage in Refsum disease are poorly known, in the present study we tested the effects of Phyt on important parameters of bioenergetics, such as the activities of the respiratory chain complexes I to IV, creatine kinase and Na(+), K(+)- ATPase in cerebellum preparations from young rats. The activities of complexes I, II, I-III and II-III and Na(+), K(+)- ATPase were markedly inhibited (65-85%) in a dose-dependent manner by Phyt. In contrast, creatine kinase and complex IV activities were not altered by this fatty acid. Therefore, it is presumed that impairment of the electron flow through the respiratory chain and inhibition of Na(+), K(+)- ATPase that is crucial for synaptic function may be involved in the pathophysiology of the cerebellar abnormalities manifested as ataxia in Refsum disease and in other peroxisomal disorders in which brain Phyt accumulates.

Phytanic acid metabolism in health and disease.

Phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) is a branched-chain fatty acid which cannot be beta-oxidized due to the presence of the first methyl group at the 3-position. Instead, phytanic acid undergoes alpha-oxidation to produce pristanic acid (2,6,10,14-tetramethylpentadecanoic acid) plus CO(2). Pristanic acid is a 2-methyl branched-chain fatty acid which can undergo beta-oxidation via sequential cycles of beta-oxidation in peroxisomes and mitochondria. The mechanism of alpha-oxidation has been resolved in recent years as reviewed in this paper, although some of the individual enzymatic steps remain to be identified. Furthermore, much has been learned in recent years about the permeability properties of the peroxisomal membrane with important consequences for the alpha-oxidation process. Finally, we present new data on the omega-oxidation of phytanic acid making use of a recently generated mouse model for Refsum disease in which the gene encoding phytanoyl-CoA 2-hydroxylase has been disrupted.

Ataxia with loss of Purkinje cells in a mouse model for Refsum disease.

Refsum disease is caused by a deficiency of phytanoyl-CoA hydroxylase (PHYH), the first enzyme of the peroxisomal alpha-oxidation system, resulting in the accumulation of the branched-chain fatty acid phytanic acid. The main clinical symptoms are polyneuropathy, cerebellar ataxia, and retinitis pigmentosa. To study the pathogenesis of Refsum disease, we generated and characterized a Phyh knockout mouse. We studied the pathological effects of phytanic acid accumulation in Phyh(-/-) mice fed a diet supplemented with phytol, the precursor of phytanic acid. Phytanic acid accumulation caused a reduction in body weight, hepatic steatosis, and testicular atrophy with loss of spermatogonia. Phenotype assessment using the SHIRPA protocol and subsequent automated gait analysis using the CatWalk system revealed unsteady gait with strongly reduced paw print area for both fore- and hindpaws and reduced base of support for the hindpaws. Histochemical analyses in the CNS showed astrocytosis and up-regulation of calcium-binding proteins. In addition, a loss of Purkinje cells in the cerebellum was observed. No demyelination was present in the CNS. Motor nerve conduction velocity measurements revealed a peripheral neuropathy. Our results show that, in the mouse, high phytanic acid levels cause a peripheral neuropathy and ataxia with loss of Purkinje cells. These findings provide important insights in the pathophysiology of Refsum disease.

Expanded HSAN4 phenotype associated with two novel mutations in NTRK1.

Hereditary sensory and autonomic neuropathy type IV (HSAN4) is a severe autosomal recessive disorder characterized by childhood onset of sensory and autonomic dysfunction leading to hyperthermia, recurrent infections and physical impairment due to complications of osteoarthritis. Cognitive impairment and aggressive behaviour is common. HSAN4 is caused by mutations in the NTRK1 gene coding for the tyrosine kinase receptor A. We present detailed description of a rare, mild HSAN4 phenotype associated with two novel NTRK1 mutations. This Swedish patient presents with an adult onset of painful Charcot arthropathy, prolonged wound healing, discrete polyneuropathy, hypohidrosis without further autonomic dysfunction and no cognitive affection.

A novel homozygous NDRG1 mutation in a Chinese patient with Charcot-Marie-Tooth disease 4D.

Charcot-Marie-Tooth disease 4D (CMT4D) is characterized by severe peripheral neuropathy and deafness. It is caused by mutations in the N-myc downstream-regulated gene 1 (NDRG1). We report a Chinese man with a homozygous mutation c.675C > T of NDRG1 that resulted in Q185X, representing the third known CMT4D patient of non-European ancestry. The patient presented with a 15-year-long history of progressive limb weakness accompanied by hearing loss and dysarthria. There was abnormal differentiation and increased interpeak latencies in brainstem auditory evoked potentials. Compound muscle action potentials (CMAP) of the peripheral nerves were not elicited in distal segments, while prolonged distal latencies and decreased CMAP were present in proximal nerves. A mild enlargement of the lateral ventricles showed in brain magnetic resonance imaging studies. Q185X of NDRG1 is a novel mutation with CMT4D, which are demonstrated in Asian population. Q185X of the NDRG1 expands the clinical and mutational spectrum of CMT4D.

Heredopathia atactica polyneuritiformis (phytanic acid storage disease). A new case with special reference to dietary treatment.

A 33-year-old man with Refsum disease exhibited clinical features of night blindness, dysequilibrium, hearing loss, itchy dry skin, symmetrical polyneuropathy, distal muscle weakness, pes cavus, and hammer toe. His total serum protein was increased, nerve conduction velocities were slow, and serum phytanic acid levels were high. Dietary restriction of phytol resulted in a decrease in serum phytanic acid without any visual and autitory changes; however, coordination, skin lesions, and nerve conduction velocities definitely improved.

Renal involvement in Refsum's disease.

Renal hemodynamic and tubular functions were measured in a patient with Refsum's disease before and after 12 weeks of twice-weekly plasmaphereses. Percutaneous renal biopsy was performed before initiation of plasmapheresis. These studies were performed to (1) define the nature of the renal lesions and the effects of phytanic acid accumulation on renal functions, and (2) assess the effects of lowering the plasma phytanic acid level on renal functions. The patient, a 39 year old woman, had lipiduria, glycosuria, cylindruria, minimal proteinuria and mild azotemia initially. Renal lesions consist of extensive vacuolization and mitochondrial changes of the tubular epithelial cells, vacuolization of the visceral epithelial cells of the glomeruli, and slight to moderate mesangial sclerosis. The impaired renal hemodynamic function and various tubular functions improved following plasmaphereses associated with reduction of plasma phytanic acid. Over-all clinical improvement was also evident.

Infantile refsum disease in four Amish sibs.

Infantile Refsum disease (IRD) appears with varying degrees of impaired vision, hearing loss, developmental delays, and neuromotor deficiencies. We report on four Amish sibs with IRD from a consanguineous marriage; biochemical testing supported the diagnosis of IRD. Of particular interest in this sibship are characteristic poorly formed yellow-orange teeth in at least three of the four affected sibs and behavior problems in the affected females.

Human peroxisomal disorders.

Peroxisomes are single membrane-bound cell organelles performing numerous metabolic functions. The present article aims to give an overview of our current knowledge about inherited peroxisomal disorders in which these organelles are lacking or one or more of their functions are impaired. They are multiorgan disorders and the nervous system is implicated in most. After a summary of the historical names and categories, each having distinct symptoms and prognosis, microscopic pathology is reviewed in detail. Data from the literature are added to experience in the authors' laboratory with 167 liver biopsy and autopsy samples from peroxisomal patients, and with a smaller number of chorion samples for prenatal diagnosis, adrenal-, kidney-, and brain samples. Various light and electron microscopic methods are used including enzyme- and immunocytochemistry, polarizing microscopy, and morphometry. Together with other laboratory investigations and clinical data, this approach continues to contribute to the diagnosis and further characterization of peroxisomal disorders, and the discovery of novel variants. When liver specimens are examined, three main groups including 9 novel variants (33 patients) are distinguished: (1) absence or (2) presence of peroxisomes, and (3) mosaic distribution of cells with and without peroxisomes (10 patients). Renal microcysts, polarizing trilamellar inclusions, and insoluble lipid in macrophages in liver, adrenal cortex, brain, and in interstitial cells of kidney are also valuable for classification. On a genetic basis, complementation of fibroblasts has classified peroxisome biogenesis disorders into 12 complementation groups. Peroxisome biogenesis genes (PEX), knock-out-mice, and induction of redundant genes are briefly reviewed, including some recent results with 4-phenylbutyrate. Finally, regulation of peroxisome expression during development and in cell cultures, and by physiological factors is discussed.

Infantile phytanic acid storage disease, a disorder of peroxisome biogenesis: a case report.

The infantile and classic forms of phytanic acid storage disease belong to the newly recognized group of peroxisomal disorders. In this paper we report the full clinical, morphological and biochemical results in a patient with infantile phytanic acid storage disease. The results indicate a generalized loss of peroxisomal functions due to a deficiency of peroxisomes as demonstrated in hepatocytes and cultured skin fibroblasts.

Supplemental therapy in isolated vitamin E deficiency improves the peripheral neuropathy and prevents the progression of ataxia.

A 24-year-old male, who suffered since childhood from a progressive form of ataxia associated with peripheral neuropathy, was found severely deficient in serum vitamin E. He walked with bilateral aid and presented severe dysmetria of the limbs and dysarthric speech; muscular strength and trophism were slightly diminished in the distal muscles of four limbs and there was hypotonia of the arms; he presented absent deep tendon reflexes, bilateral Babinski's sign, reduced proprioception at four limbs, pes cavus and fasciculations of the tongue. Intestinal fat malabsorption and other gastrointestinal or haematological conditions associated with deficiency of this vitamin were ruled out. In this patient, after 2 years of a daily supplement of high doses of vitamin E, a further progression of the disease was not observed and, moreover, the neurophysiological characteristics of his neuropathy appeared clearly improved. A longitudinal evaluation of serum vitamin E levels showed values in the normal range after 13 months of therapy. The patient had molecular genetic analysis of chromosome 8 and was found homozygous for the unusual mutation 513insTT in the alpha-tocopherol transfer protein gene.

[Refsum's disease. Ophthalmologic symptomatology dominated by tight bilateral miosis]. / Maladie de Refsum. Symptomatologie ophtalmologique dominée par un myosis bilatéral serré.

A case of Refsum's disease in a 62-year-old man, with an ophthalmologic symptomatology dominated by a tight bilateral miosis, is reported. The miosis mechanism in this disease is discussed. The clinical evolution has been stabilized by a diet poor in phytanic acid.

Electroretinographic findings in retinitis pigmentosa.

Full-field electroretinograms (ERGs) provide a basis for establishing the diagnosis of widespread progressive forms of retinitis pigmentosa in early life even at a time when fundus abnormalities visible with the ophthalmoscope are minimal or absent. Patients characteristically show delays in rod or cone b-wave implicit times or both, while patients with self-limited sector retinitis pigmentosa or stationary night blindness have normal b-wave implicit times. ERGs are presented to show their usefulness in detection of female carriers of X-chromosome-linked retinitis pigmentosa, in quantitating the natural course of all types of retinitis pigmentosa, and in detecting an abnormal rod ERG diurnal rhythm in the dominant form. Potential therapies for the retinitis pigmentosa associated with abetalipoproteinemia and Refsum's disease are also considered.

[Pauci-symptomatic sensory polyneuropathy in Refsum's disease]. / Polyneuropathie sensitive pauci-symptomatique au cours d'une maladie de Refsum.

Refsum's disease is an autosomal recessive disease caused by defective alpha-oxidation of phytanic acid. The usual clinical presentation is the association of retinitis pigmentosa, ataxia and chronic severe sensorimotor polyneuropathy. A case of mild purely sensory neuropathy in a 40-year-old patient associated to high CSF protein level led to the diagnosis of Refsum's disease. The paucity of sensory symptoms and signs of neuropathy contrasted with severe reduction of motor and sensory nerve conduction velocities and markedly signs of sensory neuropathy observed in the nerve biopsy. Typical ring-scotomas, retinitis pigmentosa, anosmia, deafness, and high plasma phytanic acid level were present in extensive examination. There was no other case in the family.

[Refsum disease]. / La maladie de Refsum.

Refsum's disease, firstly described almost 50 years ago by the Norvegian neurologist Sigvald Refsum, is an autosomic recessive disease affecting mostly the Scandinavians and the populations originating from Northern Europe. The disease results from a specific enzyme deficiency of the first step of phytanic acid catabolism pathway. This deficiency leads to an accumulation of this C20 fatty acid in the serum and the tissues with a preference for adipose tissue, liver and kidneys. The clinical picture includes retinitis pigmentosa, peripheral neuropathy, ataxia and elevated cerebrospinal fluid protein concentration. Other less frequent manifestations include cranial nerves deficiency, myocardiopathy, renal tubular dysfunction and ichtyosis. The diagnosis relies on serum phytanic acid measurement. The treatment consists of a phytanic-acid free diet sometimes associated with plasmapheresis. This treatment is generally effective on neuropathy but not on cranial nerves dysfunction and retinitis pigmentosa.

[Ophthalmological manifestations of infantile Refsum's disease: apropos of 3 cases]. / Manifestations ophtalmologiques de la maladie de Refsum infantile: à propos de trois cas.

We describe the ophthalmic manifestations of 3 cases of infantile Refsum's disease. The gravity and the aspect of the retinal disorders which we have observed by ophthalmoscopy and electroretinography were quite different from one case to another, including two siblings. We then go on to discuss the pathogeny and the genetic basis of diseases due to a deficiency of the peroxisomal biogenesis.