Primary diagnosis of Wolfram syndrome in an adult patient — Case report and description of a novel pathogenic mutation

Wolfram syndrome is a rare, autosomal recessive, neurodegenerative disorder presenting with the main clinical symptoms of childhood-onset diabetes mellitus, optic atrophy, diabetes insipidus and deafness (DIDMOAD). Later stages of the disease are dominated by neurological complications and death occurs early in life with a median life expectancy of 30 years. Here we present a 44 year old patient who presented to our hospital with central respiratory failure, cognitive impairment, ataxia and parkinsonism and was first diagnosed with Wolfram syndrome. DNA sequence analysis revealed a novel pathogenic mutation within the WFS1 gene. Advanced clinical and imaging studies performed in this patient highlight the neurodegenerative process in Wolfram syndrome and expand our knowledge on the mutational spectrum of the disease.     

Wolfram syndrome: a clinicopathologic correlation

Wolfram syndrome or DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy and deafness) is a neurodegenerative disorder characterized by diabetes mellitus and optic atrophy as well as diabetes insipidus and deafness in many cases. We report the post-mortem neuropathologic findings of a patient with Wolfram syndrome and correlate them with his clinical presentation. In the hypothalamus, neurons in the paraventricular and supraoptic nuclei were markedly decreased and minimal neurohypophyseal tissue remained in the pituitary. The pontine base and inferior olivary nucleus showed gross shrinkage and neuron loss, while the cerebellum was relatively unaffected. The visual system had moderate to marked loss of retinal ganglion neurons, commensurate loss of myelinated axons in the optic nerve, chiasm and tract, and neuron loss in the lateral geniculate nucleus but preservation of the primary visual cortex. The patient’s inner ear showed loss of the organ of Corti in the basal turn of the cochleae and mild focal atrophy of the stria vascularis. These findings correlated well with the patient’s high-frequency hearing loss. The pathologic findings correlated closely with the patient’s clinical symptoms and further support the concept of Wolfram syndrome as a neurodegenerative disorder. Our findings extend prior neuropathologic reports of Wolfram syndrome by providing contributions to our understanding of eye, inner ear and olivopontine pathology in this disease.     

Juvenile onset diabetes mellitus, central diabetes insipidus and optic atrophy (Wolfram syndrome)--neurological findings and prognostic implications.

The authors report on one case of Wolfram syndrome, a rare condition, which is characterized by juvenile onset diabetes mellitus, diabetes insipidus, optic atrophy and sensorineural deafness. The findings of this 13-year follow-up show that this patient developed typical neurological complications of long-standing diabetes mellitus as in the common type 1 variant. Moreover, some peculiar signs occurred such as anosmia, ophthalmoplegia interna, and central nystagmus. Since Wolfram syndrome is probably part of a more generalized neurodegenerative disorder, long-term prognosis will depend both upon the severity of chronic diabetic complications and upon the rapidity, by which degeneration of cerebellar, pontine and brain stem structures appear. Prognosis of the cardinal clinical signs is such that optic atrophy, though usually quite rapid in the beginning, generally does not lead to complete blindness. Sensorineural hearing loss progresses very slowly so that deafness might be expected exceptionally only. The hearing deficit in classical diabetics, however, is of retrocochlear origin. Therefore, in Wolfram syndrome, a combined inner-ear and retrocochlear hearing loss may occur.     

Evidence of widespread axonal pathology in Wolfram syndrome

Wolfram syndrome, characterised by diabetes insipidus, diabetes mellitus, optic atrophy sensorineural deafness and acquired urinary tract abnormalities, is an hereditary neurodegenerative syndrome, the pathogenesis of which is unknown. We report the post-mortem findings on a patient with well-documented Wolfram syndrome. The brain showed severe degeneration of the optic nerves, chiasm and tracts as well as severe loss of neurons from the lateral geniculate nuclei, basis pontis, and the hypothalamic paraventricular and supraoptic nuclei. In addition, there was a widespread axonal dystrophy with axonal swellings in the pontocerebellar tracts, the optic radiations, the hippocampal fornices and the deep cerebral white matter. This widespread axonal pathology parallels the pattern of neurodegeneration and in many areas is more striking than neuronal loss. Received: 18 November 1998 / Revised, accepted: 3 February 1999     

Wolfram syndrome: evidence of a diffuse neurodegenerative disease by magnetic resonance imaging.

Wolfram syndrome is an autosomal recessive disorder beginning in childhood that consists of four cardinal features: optic atrophy, diabetes mellitus, diabetes insipidus, and neurosensory hearing loss. Aside from these features, the clinical picture is highly variable and may include other neurologic abnormalities such as ataxia, nystagmus, mental retardation, and seizures. We present two unrelated patients with Wolfram syndrome, both of whom had the four cardinal features and several other neurologic abnormalities. MRIs showed widespread atrophic changes throughout the brain, some of which correlated with the major neurologic features of the syndrome.     

Wolfram's syndrome presenting as a cerebellar ataxia

INTRODUCTION: Wolfram syndrome is a genetic disease with recessive autosomic transmission, associating early-onset diabetes mellitus and bilateral optical atrophy. CASE REPORT: We report the case of a 47-year-old patient for whom we diagnosed a Wolfram syndrome in view of a late neurological syndrome in association with ataxia and bilateral horizontal nystagmus. The brain resonance magnetic imaging revealed a major atrophy of the brainstem and cerebellum. CONCLUSION: Wolfram syndrome is a rare pathology, with fatal consequences before the age of 50. The association of diabetes mellitus and optical atrophy, especially when there are other symptoms (ataxia, deafness, diabetes insipidus, neuropsychiatric manifestations or urinary tract disorders) should lead to this diagnosis and to carry out a genetic confirmation.     

Mutation screening of the Wolfram syndrome gene in psychiatric patients

Wolfram syndrome, a rare autosomal recessive neurodegenerative disorder, was originally described as a combination of familial juvenile-onset diabetes mellitus and optic atrophy. It was later demonstrated that Wolfram syndrome patients were highly prone to psychiatric disorders. Mutations in exon 8 of the Wolfram syndrome gene account for 88% of the patients with Wolfram syndrome. To examine whether the gene responsible for causing Wolfram syndrome is involved in psychiatric disorders, we screened exon 8 of the Wolfram syndrome gene for mutations in 119 patients with schizophrenia, one patient with schizoaffective disorder, 12 patients with bipolar disorder and 15 patients with major depression, using sequence analysis. In Wolfram syndrome patients, this gene has been shown to have primarily nonsense or frameshift mutations, which would result in a premature truncation of the protein. None of the psychiatric patients screened in this study carried these types of mutations. We identified, however, 24 new variations whose significance remains to be determined.     

Wolfram syndrome 1 (Wfs1) gene expression in the normal mouse visual system

Wolfram syndrome (OMIM 222300) is a neurodegenerative disorder defined by insulin-dependent diabetes mellitus and progressive optic atrophy. This syndrome has been attributed to mutations in the WFS1 gene, which codes for a putative multi-spanning membrane glycoprotein of the endoplasmic reticulum. The function of WFS1 (wolframin), the distribution of this protein in the mammalian visual system, and the pathogenesis of optic atrophy in Wolfram syndrome are unclear. In this study we made a detailed analysis of the distribution of Wfs1 mRNA and protein in the normal mouse visual system by using in situ hybridization and immunohistochemistry. The mRNA and protein were observed in the retina, optic nerve, and brain. In the retina, Wfs1 expression was strong in amacrine and Müller cells, and moderate in photoreceptors and horizontal cells. In addition, it was detectable in bipolar and retinal ganglion cells. Interestingly, moderate Wfs1 expression was seen in the optic nerve, particularly in astrocytes, while little Wfs1 was expressed in the optic chiasm or optic tract. In the brain, moderate Wfs1 expression was observed in the zonal, superficial gray, and intermediate gray layers of the superior colliculus, in the dorsomedial part of the suprachiasmatic nucleus, and in layer II of the primary and secondary visual cortices. Thus, Wfs1 mRNA and protein were widely distributed in the normal mouse visual system. This evidence may provide clues as to the physiological role of Wfs1 protein in the biology of vision, and help to explain the selective vulnerability of the optic nerve to WFS1 loss-of-function.     

Wfs1‐deficient animals have brain‐region‐specific changes of Na+, K+‐ATPase activity and mRNA expression of α1 and β1 subunits

Mutations in the WFS1 gene, which encodes the endoplasmic reticulum (ER) glycoprotein, cause Wolfram syndrome, a disease characterized by juvenile‐onset diabetes mellitus, optic atrophy, deafness, and different psychiatric abnormalities. Loss of neuronal cells and pancreatic β‐cells in Wolfram syndrome patients is probably related to the dysfunction of ER stress regulation, which leads to cell apoptosis. The present study shows that Wfs1‐deficient mice have brain‐region‐specific changes in Na⁺,K⁺‐ATPase activity and in the expression of the α₁ and β₁ subunits. We found a significant (1.6‐fold) increase of Na‐pump activity and β₁ subunit mRNA expression in mice lacking the Wfs1 gene in the temporal lobe compared with their wild‐type littermates. By contrast, exposure of mice to the elevated plus maze (EPM) model of anxiety decreased Na‐pump activity 1.3‐fold in the midbrain and dorsal striatum and 2.0‐fold in the ventral striatum of homozygous animals compared with the nonexposed group. Na‐pump α₁‐subunit mRNA was significantly decreased in the dorsal striatum and midbrain of Wfs1‐deficient homozygous animals compared with wild‐type littermates. In the temporal lobe, an increase in the activity of the Na‐pump is probably related to increased anxiety established in Wfs1‐deficient mice, whereas the blunted dopamine function in the forebrain of Wfs1‐deficient mice may be associated with a decrease of Na‐pump activity in the dorsal and ventral striatum and in the midbrain after exposure to the EPM. © 2014 Wiley Periodicals, Inc.     

Psychiatric symptoms in a patient with Wolfram syndrome caused by a combination of thalamic deficit and endocrinological pathologies

DIDMOAD or Wolfram syndrome is a hereditary disorder characterized by early onset diabetes and optic atrophy. Besides these features, a variety of other symptoms have been described including psychiatrical abnormalities leading to hospitalization in about 25% of all patients. To our knowledge, until now, a detailed characterization of these psychiatric symptoms does not exist. Here we describe a 21-year-old male patient with deficits of frontal lobe function, such as impaired impulse control and learning deficits. Magnetic resonance imaging (MRI) of the brain showed a bilateral optic atrophy, but no signs of frontal brain atrophy. Neuropsychological tests revealed performance deficits in complex planning (e.g., Tower of London). Also his capacities in memorizing logically connected information after a short and delayed period of time were significantly reduced. Since histopathological studies did not reveal frontal brain abnormalities, but did show thalamic neuronal loss and gliosis, we interpret our findings as representative of thalamic dysfunction. In addition, hypoglycaemia seemed to trigger rapid mood swings. As soon as blood glucose levels improved, the patient stabilized emotionally and assaultive behaviour disappeared while the cognitive deficits remained unchanged.     

Psychiatric disorders and mutations at the Wolfram syndrome locus.

Identifying genetic loci at which mutations predispose individuals to common psychiatric illnesses will have major impact on the diagnosis and treatment of mental illness. The available evidence indicates that mutations at the Wolfram syndrome locus contribute substantially to the prevalence of psychiatric illness in the general population. Patients with mutations at this locus on both parental chromosomes, called Wolfram syndrome homozygotes, have a distinctive and rare autosomal recessive syndrome characterized by juvenile onset diabetes mellitus and bilateral progressive optic atrophy. Diverse and serious psychiatric manifestations frequently have been observed in Wolfram syndrome patients; however, the population burden of mental illness attributable to mutations at this locus is almost entirely from individuals who carry a single mutation, called Wolfram syndrome heterozygotes, who have no distinguishing physical characteristics but constitute approximately 1% of the population. Molecular genotyping of blood relatives of Wolfram syndrome patients has shown that Wolfram syndrome heterozygotes are 26-fold more likely than noncarriers to have a psychiatric hospitalization. Severe depression was the predominant finding in the test group studied. The prediction that approximately 25% of all patients hospitalized for depression are Wolfram syndrome heterozygotes now can be tested by mutation screening of hospitalized patients from the general population. Many other behavioral and cognitive difficulties also have been observed in Wolfram syndrome families. For each specific psychiatric abnormality, a "test group" of blood relatives within Wolfram syndrome families with that abnormality can be formed. By comparing the number of Wolfram syndrome heterozygotes found in each test group by molecular genotyping with the number expected under the null hypothesis, the index-test method can determine which clinical phenotypes result from mutations at the Wolfram syndrome locus. This method can be utilized to identify other loci at which mutations predispose individuals to psychiatric illnesses.     

Familial mitochondrial encephalomyopathy with stroke-like episodes and episodic disturbances of consciousness: a study of pedigree including three generations with multisystemic abnormalities

We report here two cases in a family with pleomorphic clinical features which include mitochondrial myopathy, encephalopathy, stroke-like episodes, episodic disturbances of consciousness and other multisystemic abnormalities. The other signs observed in multisystemic abnormalities were ophthalmoplegia, short stature, diabetes mellitus, diabetes insipidus, renal dysfunction, optic atrophy, retinal degeneration, impairment of hearing and mental retardation or deterioration. A symptomatological variation was observed in cases in the same family. It is suggested that these widely varying symptoms may be expressions caused by a common biochemical defect which involves different tissues in different individuals in the family. The syndromes observed in the present cases were compared with other possibly-related mitochondrial encephalomyopathies.     

Familial Mitochondrial Encephalomyopathy with Stroke-like Episodes and Episodic Disturbances of Consciousness: A Study of Pedigree Including Three Generations with Multisystemic Abnormalities

Abstract: We report here two cases in a family with pleomorphic clinical features which include mitochondrial myopathy, encephalopathy, stroke-like episodes, episodic disturbances of consciousness and other multisystemic abnormalities. The other signs observed in multisystemic abnormalities were ophthalmoplegia, short stature, diabetes mellitus, diabetes insipidus, renal dysfunction, optic atrophy, retinal degeneration, impairment of hearing and mental retardation or deterioration. A symptomatological variation was observed in cases in the same family. It is suggested that these widely varying symptoms may be expressions caused by a common biochemical defect which involves different tissuesin different individuals in the family. The syndromes observed in the present cases were compared with other possibly-related mitochondrial encephalomyopathies.     

Gleichzeitiges Vorkommen von Diabetes mellitus,Diabetes insipidus,Opticusatrophie und Innenohrschwerhörigkeit

Summary Report of a further case with coexisting diabetes mellitus, diabetes insipidus, optic atrophy und neurogenic deafness. It was not possible to find a cause for these symptoms. The cases reported in the literature are brought together and discussed.

     

Leigh and Leigh-like syndrome in children and adults

Leigh syndrome (also termed subacute, necrotizing encephalopathy) is a devastating neurodegenerative disorder, characterized by almost identical brain changes, e.g., focal, bilaterally symmetric lesions, particularly in the basal ganglia, thalamus, and brainstem, but with considerable clinical and genetic heterogeneity. Clinically, Leigh syndrome is characterized by a wide variety of abnormalities, from severe neurologic problems to a near absence of abnormalities. Most frequently the central nervous system is affected, with psychomotor retardation, seizures, nystagmus, ophthalmoparesis, optic atrophy, ataxia, dystonia, or respiratory failure. Some patients also present with peripheral nervous system involvement, including polyneuropathy or myopathy, or non-neurologic abnormalities, e.g., diabetes, short stature, hypertrichosis, cardiomyopathy, anemia, renal failure, vomiting, or diarrhea (Leigh-like syndrome). In the majority of cases, onset is in early childhood, but in a small number of cases, adults are affected. In the majority of cases, dysfunction of the respiratory chain (particularly complexes I, II, IV, or V), of coenzyme Q, or of the pyruvate dehydrogenase complex are responsible for the disease. Associated mutations affect genes of the mitochondrial or nuclear genome. Leigh syndrome and Leigh-like syndrome are the mitochondrial disorders with the largest genetic heterogeneity.     

Familial mitochondrial intestinal pseudo-obstruction and neurogenic bladder

Intestinal dysmotility and neurogenic bladder have been described as part of two autosomal-recessive mitochondrial disorders assumed to be due to a defect in communication between the nuclear and mitochondrial genomes: myoneurogastrointestinal encephalopathy (MNGIE) and diabetes insipidus, diabetes mellitus, optic atrophy, and deafness (Wolfram syndrome). Partial cytochrome c oxidase deficiency has been described in both. We describe three Ashkenazi Jewish siblings with progressive intestinal dysmotility, neurogenic bladder, and autonomic manifestations but no central nervous system involvement. Cytochrome c oxidase deficiency was demonstrated in peripheral and multiple intestinal muscle biopsies. Mitochondrial DNA analysis of an intestinal biopsy of patient 1 showed heteroplasmy consisting of a normal 16.5-kb band and an approximately 28-kb band, suggestive of a duplication. Mitochondrial DNA analysis of a muscle biopsy of patient 2 showed multiple deletions, mainly 10- and 11-kb bands. We suggest that this unique combination of intestinal pseudo-obstruction and neurogenic bladder could comprise a new autosomal-recessive mitochondrial disorder.     

NEUROLOGICAL STUDIES IN FAMILIES WITH LEBER''S OPTIC ATROPHY

In this study 289 individuals from 5 pedigrees with Leber's optic atrophy (L. O. A.) were examined neurologically and the symptoms observed were expressed by numerical values, according to an arbitrary number scale; 34 of the 289 were patients suffering from the optic atrophy. Of these 34 patients with L. O. A., 24 were found to have minor neurological abnormalities, a finding which was corroborated by an analysis of previously published reports. A gradual decline in the percentage of individuals with abnormalities was observed in different groups in the following order: Leber patients–brothers of Leber patients–sisters of Leber patients–group of individuals connected through females to the pedigrees ("female line" group)–external control group–group of individuals connected through males to the pedigrees ("male line" group or internal control group). Three of the pedigrees were included in the study because in each of them a patient with a severe neurological disorder was present, diagnosed as spastic paraplegia (1) and multiple sclerosis (2). Evidence is presented that the association, mostly in females, of Leber's optic atrophy and a multiple sclerosis-like neurological disorder cannot be coincidental. Leber's optic atrophy seems to be an affection of the central nervous system not necessarily restricted to the optic nerves.     

Peculiar dysmorphic syndrome with orthochromatic leucodystrophy

Summary In 1968, Hooftet al. reported in three siblings a new syndrome with non-congenital microcephaly, a peculiar appearance with strikingly large ears, a severe mental retardation, a progressive optic atrophy and spasticity combined with choreo-athetotic movements.While the myelin of the peripheral nervous system was intact, the examination of the central nervous system of the eldest sibling gave the following results: severe demyelination with occasionally a tigroid pattern, a relative preservation of the axons, a dense and diffuse fibrillary gliosis, scant amounts of neutral fats (mainly perivascular), an atrophy of the optic pathways and of the cerebellar inner granular layer. At no place were calcereous deposits found.The preservation of some myelin islands does not warrent the diagnosis of a classical form ofPelizaeus-Merzbacher's disease. The clinical and anatomo-pathological features allow a differential diagnosis withCockayne's syndrome.Our cases represent a variant oforthochromatic leucodystrophy which could also be included within subgroup VI of the enlarged classification of Pelizaeus-Merzbacher's disease (Seitelberger, 1970) and beside Cockayne's syndrome.To the late Prof. R. M. Norman.     

Nerve conduction studies in spastic paraplegia,optic atrophy,and neuropathy (SPOAN) syndrome

Introduction: SPOAN (spastic paraplegia, optic atrophy, and neuropathy) syndrome is an autosomal recessive neurodegenerative disorder identified in a large consanguineous Brazilian family. Methods: Twenty‐seven patients with SPOAN syndrome (20 women), aged 4–58 years, underwent nerve conduction studies (NCS) of the median, ulnar, tibial, and fibular nerves, and sensory NCS of the median, ulnar, radial, sural, and superficial fibular nerves. Results: Sensory nerve action potentials were absent in the lower limbs and absent in >80% of upper limbs. Motor NCS had reduced amplitudes and borderline velocities in the upper limbs and absent compound muscle action potentials (CMAPs) in the lower limbs. Conclusions: The neuropathy in SPOAN syndrome is a severe, early‐onset sensory–motor axonal polyneuropathy. Normal NCS seem to rule‐out this condition. Muscle Nerve 49 : 131–133, 2014     

Involuntary movements due to vitamin B12 deficiency

Abstract

Deficiency of vitamin B₁₂ produces protean effects on the nervous system, most commonly neuropathy, myelopathy, cognitive and behavioural symptoms, and optic atrophy. Involuntary movements comprise a relatively rare manifestation of this readily treatable disorder. Both adults and infants deficient in vitamin B₁₂ may present with chorea, tremor, myoclonus, Parkinsonism, dystonia, or a combination of these, which may precede diagnosis or become apparent only a few days after parenteral replacement therapy has begun. The pathogenesis of these movement disorders shows interesting parallels to certain neurodegenerative conditions. The clinical syndrome responds well to vitamin B₁₂ supplementation in most cases, and an early diagnosis is essential to reverse the haematological and neurological dysfunction characteristic of this disorder. In this article, we elucidate the association of vitamin B₁₂ deficiency with movement disorders in adults and in infants, discuss the pathogenesis of this association, review previously reported cases, and present a young adult male with severe generalized chorea that showed a salutary response to vitamin B₁₂ supplementation.