Isolated peripheral neuropathy in atypical metachromatic leukodystrophy: a recurrent mutation

BACKGROUND: Metachromatic leukodystrophy (MLD) is a genetic neurodegenerative disorder resulting from a deficiency of arylsulfatase A. Late onset forms are relatively rare. Central nervous system (CNS) involvement is characteristic at all ages. METHODS: A patient in her late 40s with peripheral neuropathy was assessed by EEG, evoked potentials, CT and nerve conduction studies. Nerve and muscle biopsy samples were investigated by electron microscopy. Arylsulfatase A activity in leukocytes and excreted cerebroside sulfate were determined. The arylsulfatase A gene was investigated for mutations using polymerase chain reaction (PCR) and DNA sequencing. The identified mutation was expressed transiently in African green monkey kidney (COS) cells to determine the effect of the mutation on arylsulfatase A activity. RESULTS: Central nervous system functions were normal. Nerve conduction velocities were decreased. Sural nerve biopsy showed inclusions typical of MLD. Arylsulfatase A was less than 5% of normal. A homozygous mutation thr286pro was identified in the arylsulfatase A gene and demonstrated to be deleterious through transient expression studies. CONCLUSIONS: Our patient has a progressive peripheral neuropathy but has apparently intact CNS function at her present age of 57 years. Biochemical, physiological and pathological findings are consistent with a diagnosis of MLD. A homozygous mutation, thr286pro, found in her arylsulfatase A gene, decreased enzyme activity to a level consistent with a late onset form of MLD.     

Adult-type metachromatic leukodystrophy with compound heterozygous ARSA mutations: a case report and phenotypic comparison with a previously reported case

Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disease caused by a deficiency of arylsulfatase A. MLD is a heterogeneous disease with variable age at onset and variable clinical features. We evaluated a 33-year-old female patient who developed manifestations of disinhibitory behavior. She was diagnosed with MLD by genetic analysis, which revealed compound heterozygous ARSA missense mutations (p.G99D and p.T409I). The same combination of mutations was previously reported in a Japanese patient with similar symptoms. We performed additional, detailed neuropsychological tests with functional imaging on the current patient that demonstrated frontal lobe dysfunction. These results indicate that the mutations have important implications for genotype-phenotype correlation in MLD.     

Neurological, dermatological and biological manifestations of porphyria variegata. A study of 3 families of Italian origin in Marseilles area]

Three kindreds of Italian descent with variegate porphyria are described. These families are now living in Marseilles and surrounding regions. The first kindred originating from Torre del Greco, near Naples, is living in Arles. This family includes two propositi who experienced an acute attack with visceral and neuropsychiatric manifestations. The family's survey was carried out by measuring protoporphyrogen oxidase (PO) activity in lymphocytes (normal values = 4.8 +/- 1.2). Seven of the 20 subjects tested, beside the two propositi, were found to be asymptomatic carriers (PO < 3.6). The first index patient, a 41-year old man, was first observed at the age of 31 with acute and psychiatric manifestations after rifampicin treatment; the cutaneous symptoms appeared one year later. For the second propositus, a woman presenting with abdominal and psychiatric manifestations, the age of onset was 38 years; the acute attack had no recognizable cause; she had mild skin lesions and initially was incorrectly diagnosed as intermittent acute porphyria; the diagnosis of variegate porphyria was only established at the age of 50 years. The second family, originating from la Spezia and Vernazza, is living in Marseilles. The propositus, a 50-year old man, developed cutaneous symptoms at the age of 30. A diagnosis of porphyria cutanea tarda was initially made. The first and unique acute attack with abdominal and neurological manifestations recurred at the age of 41. The diagnosis of variegate porphyria was established on laboratory data. Physical stress was probably the cause of the acute attack. Beside the propositus, out of 9 subjects tested 6 were asymptomatic carriers.(ABSTRACT TRUNCATED AT 250 WORDS)     

Seizures as a presenting feature of late onset metachromatic leukodystrophy

OBJECTIVES: We describe 2 patients with epilepsy as an early manifestation of late onset metachromatic leukodystrophy (MLD). METHODS AND RESULTS: The first patient presented with epileptic seizures at the age of 34 years while neurological and cognitive abnormalities appeared later. MRI findings were compatible with leukodystrophy and low levels of arylsulphatase-A activity confirmed MLD. The second patient developed epileptic seizures and behavioral disturbances at the age of 19 years. She remained stable and seizure free for 8 years. Afterwards she developed uncontrolled epileptic seizures and status epilepticus as well as neurological and cognitive impairment. Leukodystrophy was diagnosed by MRI findings and low levels of arylsulphatase-A activity were compatible with MLD. CONCLUSION: Our 2 cases postulate that epileptic seizures may be an early and prominent manifestation of late onset MLD.     

An Italian Cohort Study Identifies Four New Pathologic Mutations in the ARSA Gene

Metachromatic leukodystrophy is an autosomal recessive neurodegenerative disorder of the myelin metabolism due to the impaired function of the lysosomal enzyme arylsulfatase A. Three major clinical variants of metachromatic leukodystrophy (MLD) have been described: late infantile, juvenile, and late onset. The infantile form, whose clinical onset is usually before the age of 2 years, is the most frequent. The juvenile form manifests itself between 3 and 16 years and the late-onset form manifests at any time after puberty. As of today, more than 150 mutations causing MLD have been identified in the ARSA gene that encodes arylsulfatase A. In this paper, we report our experience with the diagnosis of MLD in seven Italian patients from unrelated families. We found 11 different mutations, four of which have not been previously described: c.1215_1223del9 (p.406_408del), c.601 T>C (p.Tyr201His), c.655 T>A (p.Phe219Ile), and c.87C>A (p.Asp29Glu). Our data show once more that there are still several mutations to be discovered in the ARSA gene and there are rarely repeating ones found in the population. The predictive value of the enzyme activity tests in regard to clinical manifestations is extremely limited.     

Gallbladder cancer with ascites in a child with metachromatic leukodystrophy

IntroductionMetachromatic leukodystrophy (MLD) refers to leukodystrophy caused by the accumulation of sulfatide from arylsulfatase A (ARSA) gene mutations. Sulfatide also accumulates in various organs, including the peripheral nerves, kidney, and gallbladder.Proliferative changes in the gallbladder have been reported in several patients, while gallbladder cancer is reported in only two adult MLD cases. We report what is likely the first pediatric case of MLD with gallbladder cancer.Case reportThe patient was a 5-year-old girl diagnosed with MLD using head magnetic resonance imaging and detecting a homozygous mutation of c.302G>A (p.Gly101Asp) in ARSA. Abdominal bloating was observed at the age of 4 years; CT revealed a giant tumor in the gallbladder and massive ascites. Cholecystectomy was performed and pathological examination revealed adenocarcinoma. Measurement of serum sulfatide revealed increased levels compared to the average healthy range.DiscussionRapidly increased ascites and large polyps which are reported as risk factors for cancer were characteristic in our MLD case. When such lesions are detected, they should be removed immediately because of the possibility of cancer, even in a pediatric patient.     

Adult metachromatic leukodystrophy. Value of computed tomographic scanning and magnetic resonance imaging of the brain

Patients with adult-onset metachromatic leukodystrophy (MLD) often present with personality changes or deterioration of cognitive functions. Although rare, this form of MLD should be included in the differential diagnosis of psychotic and dementing disorders. The following case report describes a 38-year-old man with adult-onset MLD, who carried the diagnosis of schizophrenia and was treated as a schizophrenic for a number of years. Metachromatic leukodystrophy was initially suspected because of white matter abnormalities detected on computed tomographic scans and magnetic resonance images of the brain. The diagnosis of MLD was confirmed by the discovery of markedly reduced leukocyte arylsulfatase A activity. The computed tomographic and magnetic resonance imaging findings in MLD are reviewed.     

Crohn's disease presenting with recurrent acute polyradiculoneuropathy

INTRODUCTION: The neurological manifestations of Crohn's disease are rare, dominated by multiple mononeuropathies and the abnormalities of the white matter. Polyradiculoneurities remain exceptional. OBSERVATIONS: We report the case of a 33-year-old patient admitted for an ascending weakness of all four limbs. Eight years earlier he had presented a similar episode which had regressed spontaneously. The neurological examination revealed a tetraparesis with areflexia and hypotonia. These manifestations were concomitant with chronic diarrhea which had been neglected to date. The electrophysiological aspect was compatible with an acute polyradiculoneuritis. The analysis of the cerebrospinal fluid showed an albumino-cytological dissociation. The existence of the diarrhea directed the investigations towards an inflammatory enteropathy, which was attested later on by the endoscopic, radiologic and histological data leading to the diagnosis of active Crohn's disease. The diagnosis of a relapsing polyradiculoneuritis associated with Crohn's disease was retained. The patient was treated by salazopyrine-budesonide with improvement in the digestive and neurological manifestations after 3 years. CONCLUSION: The frequency of neurological features in Crohn's disease is not well documented. The incriminated mechanisms are either directly related to the disease (deficit in B12 vitamin or folic acid and/or by the means of an auto-immune vascularitis) or secondary to long-term treatment with metronidazole. The course of neurological manifestations is largely dependent on the course of the inflammatory disease.     

Kindstötung und hebephrenes Syndrom bei metachromatischer Leukodystrophie

We report a patient with metachromatic leukodystrophy (MLD) with a first manifestation of homicide. On admission the patient showed a hebephrenia-like syndrome with inappropriate affect, thought disorder and behavioral changes. Magnetic resonance tomography (MRT) findings suggested a diagnosis of MLD, which was confirmed by a decreased activity of leucocyte arylsulfatase A and an excessive urinary sulfatide excretion.     

Transient ischaemic attack: a common initial manifestation of cardiac myxomas

BACKGROUND AND AIMS: Cardiac myxomas may present clinically with many different features. Since highly effective treatments exist, it is important that they are diagnosed quickly in order to avoid further complications. Our aim was to determine the influence of neurological presentation in diagnosis and prognosis of cardiac myxomas. METHODS: We have reviewed the clinical charts of 28 patients diagnosed with cardiac myxomas seen at our centre in the last 20 years. RESULTS: Mean age at diagnosis in patients with neurological events was 49.22 years and 60.84 years in those without neurological manifestations (p = 0.0325). Most frequent presentations were: cardiac manifestations (92.8%), general manifestations (71.4%) and embolic events (39.3%). Nine patients (32.1%) presented with cerebral embolism; 7 of whom presented with transient ischaemic attacks (TIA), which was the first manifestation in 6 of them; 3 of them later suffered complete cerebral infarction with sequelae. Echocardiography confirmed diagnosis in 26 out of 27 patients in which it was performed. None of the patients presented neurological symptoms after surgery. CONCLUSION: The most frequent initial neurological manifestation in our series was TIA. Nevertheless, none of the patients were diagnosed after the first neurological symptom. Although the contribution of cardiac myxomas to the total amount of TIA is low, since surgery is highly effective and of low risk, and patients with neurological manifestations are younger, it is vital to consider the possibility of cardiac myxoma after a TIA of unknown origin.     

Multipotential neural precursors transplanted into the metachromatic leukodystrophy brain fail to generate oligodendrocytes but contribute to limit brain dysfunction

Neural stem cells appear to be best suited for regenerative therapy in neurological diseases. However, the effects of high levels of potentially toxic substances such as sulfatides--which accumulate in metachromatic leukodystrophy (MLD)--on this regenerative ability are still largely unclear. To start addressing this question, in vitro and in vivo experiments were used to examine the behavior of multipotential neural precursors exposed to abnormally high levels of sulfatides. Following transplantation of dissociated neurospheres into the brain of presymptomatic MLD pups, the majority of donor-derived cells were distributed in a caudal to rostral direction, with higher numbers in the cortex. Most if not all of the donor cells acquired an astroglial phenotype. We found no evidence of oligodendrocyte or neuronal commitment of transplanted cells in long-term-treated MLD mice (e.g. up to 1.5 years of age). This was in line with our in vitro findings of sulfatides blocking oligodendrocyte formation after induction of differentiation in sulfatide-treated epidermal growth factor/fibroblast growth factor responsive neurospheres. Transplanted MLD mice showed an improved arylsulfatase A (ARSA) activity and a significant amelioration of sulfatide metabolism, neurodegeneration and motor-learning/memory deficits. Furthermore, transplanted cells were shown to act as a source of ARSA enzyme that accumulated in endogenous brain cells, indicating the occurrence of enzyme cross-correction between transplanted and host cells. These results provide a first insight into the effect of sulfatides on the stemness properties of neural stem cells and on the effects of the MLD environment on the in vivo expectations of using neural stem cells in cell therapy.     

Zinc in the treatment of hepatolenticular degeneration: report of 3 cases]

Three patients with symptoms and signs of hepatolenticular degeneration (HLD) who developed serious renal side effects of D-penicillamine (DP) had their therapeutic schedule changed to zinc. Patient 1, a 55 year-old man had been well until 12 years old, when skeletal changes (osteomalacia) due to tubular renal disturbance began. His diagnosis of HLD had first been established at age of 32 when he presented with "wing-beat" tremor. He was then begun on DP and his neurological symptoms resolved within one year of initiating therapy but skeletal abnormalities remained unchanged as a sequel. During the next 22 years the patient was continued on DP therapy but with poor compliance. Then the reappearance of his neurological manifestations occurred several times. By the age of 53, after one year without therapy, his neurological status has worse. DP was reinstituted but some weeks later his renal laboratory parameters became severely affected. DP was discontinued and zinc sulfate (220 mg three times daily) was introduced. On this therapeutic regimen his renal laboratory parameters returned to previous level after one month. Within one year on this therapeutic regimen neurological manifestations were resolved. After 31 months on zinc treatment he remains neurologically asymptomatic and his renal function is satisfactory. Patient 2, a 41 year old woman had been her diagnosis of HLD at age of 20, when following the diagnosis of the disease in her old brother, she was found to have the laboratory features of HLD and bilateral Kayser-Fleischer rings. DP treatment was recommended at that time but she quit the follow-up. When she was 23, an esophageal variceal bleeding occurred.(ABSTRACT TRUNCATED AT 250 WORDS)     

Leukodystrophy Presenting as Acute-Onset Polyradiculoneuropathy

BackgroundSulfatides, the most abundant glycosphingolipids, are a major component of myelin. They are degraded by the combined action of sphingolipid activator protein and arylsulfatase A. Deficiency of either of these entities causes metachromatic leukodystrophy (MLD). On the basis of age of onset, this entity is divided into late infantile, juvenile, and adult subtypes. Late infantile form, the commonest subtype, can exhibit peripheral neuropathy as the initial manifestation. The other two forms usually manifest peripheral neuropathy later in the disease course.PatientA 1.5-year-old girl with preexisting isolated motor delay presented with acute-onset ascending flaccid quadriparesis, ptosis, and respiratory failure. Ptosis and respiratory failure responded completely to intravenous immunoglobulin, whereas quadriparesis showed minimal improvement. Nerve biopsy revealed metachromatic granules with demyelination, and serum arylsulfatase A levels were undetectable.ConclusionThe severity and nature of the disease coupled with the response to immunotherapy makes this case unusual. This child may represent either an atypical presentation of MLD with coincidental response to immunotherapy or an episode of immune mediated neuropathy in an individual with already diseased nerves due to MLD.     

Neurotoxicity due to methotrexate in paediatric patients. Description of the clinical symptoms and neuroimaging findings

INTRODUCTION. High-dose methotrexate (MTX) has showed to increase the surveillance in children with acute lymphoblastic leukemia and other neoplasms. However, MTX may induce significant neurotoxicity. AIM. To evaluate, in our population of patients who have been treated with MTX, the incidence of neurotoxicity and to describe its main clinical and radiological characteristics. PATIENTS AND METHODS. We retrospectively review the patients who received treatment with systemic high-dose MTX and/or intrathecal MTX between 1994 and 2010. The children who presented clinical o radiological signs of neurotoxicity were reviewed. RESULTS. We identified 284 patients who received high-dose intravenous and/or intrathecal MTX. 9 patients presented neurotoxicity. The median age at diagnosis was 6 years; 6 patients were male. The diagnosis included: 6 acute lymphoblastic leukemia, 2 medulloblastoma and 1 lymphoma. 66% patients presented focal neurological dysfunction, 3 had non-specific symptoms. In 5 patients the symptomatology started the first 14 days after the MTX administration. 8 patients had complete clinical resolution, but only one presented neurological long term effects. All the patients except one showed signs of acute leukoencephalopathy in the brain MR study. These alterations resolved one year later in 3 patients; in the other patients the MR alterations persisted. The neurotoxicity management was corticosteroid, folinic acid, aminophylline and dextromethorphan. CONCLUSION. The MTX neurotoxicity it can present as acute or chronic. It has a wide clinical spectrum, ranging from sub-clinical manifestations with complete recovery to a chronic and progressive encephalopathy.     

Adult metachromatic leukodystrophy: disorganized schizophrenia-like symptoms and postpartum depression in 2 sisters

We describe the cases of 2 sisters with adult metachromatic leukodystrophy (MLD). Whereas one sister presented with disorganized schizophrenia-like symptoms as the initial manifestation of MLD, the other remained symptom free except for a 4-week period of postpartum depression. In both patients, there was some residual activity of leukocyte arylsulfatase A (1.7% and 5.5% of normal), and a marked increase in urinary sulfatides was present, as measured by tandem mass spectrometry. An arylsulfatase A pseudodeficiency was therefore excluded. The most common mutations of the adult phenotype, Ile-179-Ser and Pro-426-Leu, were not found. In the literature, only 1 case of adult MLD manifesting as disorganized schizophrenia-like symptoms has been described, whereas postpartum depression has been so far unknown as a presenting symptom of MLD.     

Increased concentration of the CSF Tau protein and its phosphorylated form in the late juvenile metachromatic leukodystrophy form: a case report

Metachromatic leukodystrophy (MLD) is an autosomal recessive, lysosomal storage disease due to deficiency or absence of arylsulfatase A enzyme (ASA) with sulfatide accumulation in the central and peripheral nervous system, kidneys, and gallbladder, leading to many dysfunctions. One of the clinical forms of the disease is a late juvenile MLD. To our best knowledge, this is the first report describing increased Tau/pTau and normal Aβ1-42 concentrations in the CSF of the late juvenile MLD patient.     

Dementia with impaired temporal glucose metabolism in late-onset metachromatic leukodystrophy

An unusual case of very-late-onset metachromatic leukodystrophy (MLD) with dementia was studied. The patient was a 41-year-old male who presented with mild dementia and a single generalized tonic clonic seizure. Neuropsychological assessment demonstrated mild amnesia, visuospatial dysfunction and attention deficits with a slow psychomotor speed. MR brain imaging displayed confluent hyperintensities of periventricular and subcortical white matter. Low levels of arylsulfatase A confirmed the diagnosis. Impaired cortical glucose metabolism especially of the medial temporal and frontal cortices was observed using positron emission tomography and fluor-18-labeled fluorodesoxyglucose. The neuropsychological deficits are related to the location of deficits in glucose metabolism.     

Neurological long-term follow-up in left atrial myxoma: Are late complications frequent or rare?

Summary Neurological manifestations were analysed in 13 patients with left atrial myxoma confirmed by histological study. In this group, 6 patients had neurological complaints at initial presentation, 5 had cardiac symptoms, and 4 patients presented with signs of systemic disease. CT was performed in 10 and MRI in 7 patients. There were signs of ischaemic or haemorrhagic infarction (6 of 12) and one lesion suggestive of myxoma metastasis; other findings mainly comprised non-specific white matter lesions revealed by MRI. Neurological follow-up 0.5–8 years after tumour resection revealed no delayed neurological complications, follow-up CT and MRI findings were not suggestive of lesions acquired after operation. It is suggested that this rare condition of cardiac myxoma should be suspected in young patients with CNS symptoms or signs lacking cerebrovascular or cardiovascular risk factors and should be included in the differential diagnosis of vasculitis. With timely diagnosis and resection of the cardiac tumour the long-term prognosis can be considered improved.     

Post-cranial irradiation syndrome with migraine-like headaches, prolonged and reversible neurological deficits and seizures.

Two adult patients with a background history of astrocytomas treated with resection and cranial irradiation, 18 and 16 years previously, presented with acute onset of headache associated with prolonged neurological deficits, including dysphasia and right hemiparesis. The first patient also developed seizures while in hospital. In both patients, magnetic resonance imaging brain scans failed to show evidence of acute ischaemia or tumour recurrence and symptoms reversed completely after 1 month and 7 days, respectively. A single photon emission computed tomography scan, performed on the first patient at day 8 post-admission, showed hyperperfusion in the left parieto-occipital region (in the same region as his previous tumour). The clinical histories and outcomes are consistent with the diagnosis of post-cranial irradiation syndrome with migraine-like headaches and prolonged and reversible neurological deficits. Recognition of this disorder is useful in providing reassurance of a favourable prognosis and may also help avoid invasive investigations.