ATP13A2 mutations (PARK9) cause neurodegeneration with brain iron accumulation

Kufor Rakeb disease (KRD, PARK9) is an autosomal recessive extrapyramidal‐pyramidal syndrome with generalized brain atrophy due to ATP13A2 gene mutations. We report clinical details and investigational results focusing on radiological findings of a genetically‐proven KRD case. Clinically, there was early onset levodopa‐responsive dystonia‐parkinsonism with pyramidal signs and eye movement abnormalities. Brain MRI revealed generalized atrophy and putaminal and caudate iron accumulation bilaterally. Our findings add KRD to the group of syndromes of neurodegeneration with brain iron accumulation (NBIA). KRD should be considered in patients with dystonia‐parkinsonism with iron on brain imaging and we suggest classifying as NBIA type 3. © 2010 Movement Disorder Society     

Long-term follow-up in infantile-onset SCAR18: A case report

Autosomal recessive spinocerebellar ataxia type 18 (SCAR18) is caused by pathogenic variants in the Glutamate Receptor, Ionotropic, Delta-2 (GRID2) gene. We describe the long-term follow-up from 1 to 31 years of an Italian patient with congenital SCAR18 who is compound heterozygous for a maternally-inherited nonsense variant and a de novo microdeletion. To date, this is the longest follow-up in congenital SCAR18.     

Use of desferrioxamine in the treatment of aceruloplasminemia

Aceruloplasminemia is a newly recognized autosomal recessive disorder of iron metabolism resulting in neurodegeneration of the retina and basal ganglia. We report here on the treatment of a patient who developed progressive extrapyramidal symptoms that included blepharospasm, grimacing, and rigidity associated with increased iron deposition in the brain and visceral organs. Treatment for 10 months with the iron chelator desferrioxamine decreased brain iron stores, prevented progression of the neurological symptoms, and reduced plasma lipid peroxidation. These data suggest that early treatment with this chelator may be useful in such patients to diminish central nervous system iron accumulation and to prevent or ameliorate neurological symptoms associated with neurodegeneration.     

Late-onset nonketotic hyperglycinemia: a case report]

We report a 66-year-old woman who developed mental deterioration in her school days, and progressive gait disturbance, dysarthria and bradykinesia in her 40 s. Her parents were consanguineous, and the two of her brothers were suspected to have the allied disorder. On physical examination, she was short-statured and high-arched palate was observed. Neurological examination revealed dementia, abnormal eye movement, dysarthria, spastic paraparesis with hyperreflexia, bilateral Babinski signs, cerebellar ataxia and dysuria. Brain MRI showed marked hypoplasia of corpus callosum with dilatation of lateral ventricles and cerebral sulci and significant cerebellar atrophy. Amino acid analyses showed significant elevation of glycine without ketosis in serum, cerebrospinal fluid, and urine, which lead us to the diagnosis of late-onset nonketotic hyperglycinemia(NKH). NKH is known to be a rare autosomal recessive metabolic disorder primarily caused by deficient activity of various components of the mitochondrial glycine cleavage system. Onset of the disease occurs most often in early infancy, however, later-onset variants have been described. Usually, late-onset NKH only manifests mild mental deterioration, character change, seizure, ataxia or spastic paraparesis, which sometimes makes difficulty in differentiating this disease from other hereditary cerebellar ataxia or spastic paraparesis. In addition, many structural brain abnormalities have been reported accompanied with NKH, and especially, agenesis or hypoplasia of corpus callosum is the most characteristic feature in this disease. Therefore, we emphasized that amino acid analyses should be considered in any patients who have cerebellar ataxia or spastic paraparesis of unknown cause with these neuroradiological findings.     

Neurodegeneration with brain iron accumulation

Neurodegeneration with brain iron accumulation (NBIA) describes a group of progressive extrapyramidal disorders with radiographic evidence of focal iron accumulation in the brain, usually in the basal ganglia. Patients previously diagnosed with Hallervorden-Spatz syndrome fall into this category. Mutations in the PANK2 gene account for the majority of NBIA cases and cause an autosomal recessive inborn error of coenzyme A metabolism called pantothenate kinase-associated neurodegeneration (PKAN). PKAN is characterized by dystonia and pigmentary retinopathy in children or speech and neuropsychiatric disorders in adults. In addition, a specific pattern on brain MRI, called the eye-of-the-tiger sign, is virtually pathognomonic for the disease. Pantothenate kinase is essential to coenzyme A biosynthesis, and the PANK2 protein is targeted to the mitochondria. Hypotheses of PKAN pathogenesis are based on the predictions of tissue-specific coenzyme A deficiency and the accumulation of cysteine-containing substrates. Identification of the major NBIA gene has led to more accurate clinical delineation of the diseases that comprise this group, a molecular diagnostic test for PKAN, and hypotheses for treatment.     

C19orf12 mutations in neurodegeneration with brain iron accumulation mimicking juvenile amyotrophic lateral sclerosis

Mutations in C19orf12 have been recently identified as the molecular genetic cause of a subtype of neurodegeneration with brain iron accumulation (NBIA). Given the mitochondrial localization of the gene product the new NBIA subtype was designated mitochondrial membrane protein-associated neurodegeneration. Frequent features in the patients described so far included extrapyramidal signs and pyramidal tract involvement. Here, we report three C19orf12-mutant patients from two families presenting with predominant upper and lower motor neuron dysfunction mimicking amyotrophic lateral sclerosis with juvenile onset. While extrapyramidal signs were absent, all patients showed neuropsychological abnormalities with disinhibited or impulsive behavior. Optic atrophy was present in the simplex case. T2-weighted cranial MRI showed hypointensities suggestive of iron accumulation in the globi pallidi and the midbrain in all patients. Sequence analysis of C19orf12 revealed a novel mutation, p.Gly66del, compound heterozygous with known mutations in all patients. These patients highlight that C19orf12 defects should be considered as a differential diagnosis in patients with juvenile onset motor neuron diseases. Patients have to be examined carefully for neuropsychological abnormalities, optic neuropathy, and signs of brain iron accumulation in MRI.     

Mutations in <Emphasis Type="Italic">GALC</Emphasis> cause late-onset Krabbe disease with predominant cerebellar ataxia

Mutations in GALC cause Krabbe disease. This autosomal recessive leukodystrophy generally presents in early infancy as a severe disorder, but sometimes manifests as a milder adult-onset disease with spastic paraplegia as the main symptom. We recruited a family with five affected individuals presenting with adult-onset predominant cerebellar ataxia with mild spasticity. Whole exome sequencing (WES) revealed one novel and one previously reported compound heterozygous variants in GALC. Magnetic resonance imaging (MRI) confirmed the presence of typical Krabbe features. Our findings expand the phenotypic spectrum of adult-onset Krabbe disease and demonstrate the usefulness of combining WES and pattern-specific MRI for the diagnosis of neurodegenerative diseases.     

Does brain degeneration in Wilson disease involve not only copper but also iron accumulation?

Background and purposeWilson disease (WD) is an autosomal recessive inherited disorder of hepatic copper metabolism. Clinical manifestations of WD include neurologic, hepatic and psychiatric symptoms. Most WD patients with the neuropsychiatric form, and some with the hepatic and presymptomatic forms have both hypointense and hyperintense lesions in basal ganglia on T2-weighted magnetic resonance imaging (MRI), which can be iron and copper accumulation. It has been established that T2* and susceptibility-weighted imaging (SWI) are highly sensitive in demonstrating brain iron accumulation, showing decreased signal intensity. Hypointense globus pallidus (GP) signal has been described on T2-, T2*-weighted images and on SWI as typical MRI lesion for patients with neurodegeneration with brain iron accumulation (NBIA). We investigated whether WD patients have MRI changes suggesting iron accumulation using T2*-weighted and VEN_BOLD SWI imaging protocols.Material and methodsStandard MRI with additional sequences (T2*-weighted and VEN_BOLD SWI) was performed in consecutively admitted, clinically stable, and treated patients.ResultsTwenty-eight patients entered the study. Hypointensity in the GP was observed on T2*-weighted images in 10 patients. Using the VEN_BOLD SWI technique, we found hypointense signal in GP in 20 patients.ConclusionsMRI data suggest not only copper but also iron accumulation in GP in WD patients.     

Absence of mutations in ATM, the gene responsible for ataxia telangiectasia in patients with cerebellar ataxia

Ataxia-telangiectasia (AT) is an autosomal recessive multisystent disorder presenting in childhood with progressive cerebellar ataxia, oculocutaneous telangiectasia, immune deficiency, radiosensitivity, and cancer predisposition. The gene for AT, designated ATM (AT, mutated) encodes a protein with a carboxy-terminal phosphoinositide-3 kinase domain which is involved in cell cycle checkpoints and other responses to genotoxic stress. Most of the patients with the classical AT phenotype are homozygous or compound heterozygous for severe mutations causing truncation or destabilization of the ATM protein. Patients with a milder forms of disease, called AT variants, have been found to be either homozygous for milder mutations or compound heterozygotes for null alleles and mild mutations. In order to define the clinical phenotype of patients homozygous (or compound heterozygotes) for other, milder mutations, we decided to search for ATM mutations in patients with either sporadic or familial idiopathic ataxia. Thirty-four patients with idiopathic cerebellar ataxia, aged 3–77 years, were screened for mutations in the ATM coding region. There were 12 familial cases. None of the patients had abnormal immunoglobulin or α-fetoprotein levels, and none had mutations in the ATM coding region. In this heterogeneous group of patients with cerebellar ataxia we found no mutations in the ATM gene. We conclude that mutations in the ATM gene are probably not a common cause for cerebellar ataxia other than AT. Received: 29 October 1998 Received in revised form: 5 February 1999 Accepted: 7 February 1999     

Clinical and genetic study of autosomal recessive cerebellar ataxia type 1

OBJECTIVE: Define the phenotype and genotype of a cluster of families with a relatively pure cerebellar ataxia referred to as autosomal recessive cerebellar ataxia type 1 (ARCA-1). METHODS: We ascertained 64 probands and affected members of 30 French-Canadian families all showing similar clinical features and originating from the same region of Quebec. After informed consent, we performed detailed clinical history, neurological examination, brain imaging, nerve conduction studies, and SYNE1 mutation detection of all available subjects. RESULTS: Based on the cases examined, ARCA-1 is a cerebellar syndrome characterized by recessive transmission, middle-age onset (mean, 31.60; range, 17-46 years), slow progression and moderate disability, significant dysarthria, mild oculomotor abnormalities, occasional brisk reflexes in the lower extremities, normal nerve conduction studies, and diffuse cerebellar atrophy on imaging. We identified a total of seven mutations in our population, thereby providing evidence of genotypic heterogeneity. Patients with different mutations did not show significant phenotypic heterogeneity. INTERPRETATION: We identified a cluster of French-Canadian families with a new recessive ataxia of relatively pure cerebellar type caused by mutations in SYNE1. The function of SYNE1 is thus critical in the maintenance of cerebellar structure in humans. We expect that this disease will be a common cause of middle-age-onset recessive ataxia worldwide.     

ANO10 mutations cause ataxia and coenzyme Q10 deficiency

Inherited ataxias are heterogeneous disorders affecting both children and adults, with over 40 different causative genes, making molecular genetic diagnosis challenging. Although recent advances in next-generation sequencing have significantly improved mutation detection, few treatments exist for patients with inherited ataxia. In two patients with adult-onset cerebellar ataxia and coenzyme Q₁₀ (CoQ₁₀) deficiency in muscle, whole exome sequencing revealed mutations in ANO10, which encodes anoctamin 10, a member of a family of putative calcium-activated chloride channels, and the causative gene for autosomal recessive spinocerebellar ataxia-10 (SCAR10). Both patients presented with slowly progressive ataxia and dysarthria leading to severe disability in the sixth decade. Epilepsy and learning difficulties were also present in one patient, while retinal degeneration and cataract were present in the other. The detection of mutations in ANO10 in our patients indicate that ANO10 defects cause secondary low CoQ₁₀ and SCAR10 patients may benefit from CoQ₁₀ supplementation.     

Dominantly inherited nonprogressive cerebellar hypoplasia identified in utero

Cerebellar hypoplasia is the hallmark of a heterogeneous group of disorders that are caused by genetic and metabolic disorders. Prenatal identification of cerebellar hypoplasia and accurate prediction of outcome are challenging. Autosomal dominant nonprogressive cerebellar ataxia is a rare disorder that typically presents with early hypotonia and delayed motor milestones followed by the onset of mild ataxia and occasionally cognitive impairment. We present a case of a mother and her female fetus. Fetal sonography and magnetic resonance imaging (MRI) showed generalized cerebellar hypoplasia. The mother had mild learning difficulties and clinically showed minor features of cerebellar ataxia. Her MRI also demonstrated extreme cerebellar hypoplasia. The diagnosis of autosomal dominant nonprogressive cerebellar ataxia was suggested. This is the first report of prenatal diagnosis of autosomal dominant nonprogressive cerebellar ataxia. We recommend obtaining a family history, examining the parents, and when appropriate obtaining an MRI before counseling parents of a fetus with a brain malformation.     

Autosomal recessive spino-olivo-cerebellar degeneration without ataxia.

Five adult siblings from a sibship of ten suffering from an external ophthalmoplegia with a spastic paraplegia are reported. In addition, optic nerve atrophy was present in three of the patients and dementia in two; extrapyramidal signs and cerebellar ataxia were found only in one patient. Contrary to earlier studies of patients with comparable neurological signs the pattern of inheritance was autosomal recessive. Neuropathological investigation of the index case, who had never shown ataxia, nevertheless showed demyelination of the spinocerebellar and the olivocerebellar pathways, and also a severe loss of Purkinje cells, of cells in Clarke's column and in the inferior olives. The dentate nucleus was severely gliotic but showed no cell loss. Earlier neuropathological investigations of this disorder, but with an autosomal dominant heredity, were incomplete. It is concluded that the five siblings of this family have a unique autosomal recessive disorder, which should be considered a distinct entity.     

Exome sequencing in a family with intellectual disability, early onset spasticity, and cerebellar atrophy detects a novel mutation in EXOSC3

Whole exome sequencing in two-generational kindred from Bangladesh with early onset spasticity, mild intellectual disability, distal amyotrophy, and cerebellar atrophy transmitted as an autosomal recessive trait identified the following two missense mutations in the EXOSC3 gene: a novel p.V80F mutation and a known p.D132A change previously associated with mild variants of pontocerebellar hypoplasia type 1. This study confirms the involvement of RNA processing proteins in disorders with motor neuron and cerebellar degeneration overlapping with spinocerebellar ataxia 36 and rare forms of hereditary spastic paraplegia with cerebellar features.     

Autosomal recessive late onset multisystem disorder with cerebellar cortical atrophy at necropsy: report of a family.

A sister and brother developed a progressive syndrome comprising bulbar palsy, supranuclear ophthalmoplegia, facial impassivity, and cerebellar ataxia together with a mixed pyramidal and extrapyramidal deficit in the limbs, in the fourth decade of life. Their parents were unaffected and inheritance was probably autosomal recessive. The female patient, who presented initially with bulbar and extrapyramidal dysfunction, was found to have cerebellar cortical atrophy at necropsy. The basal ganglia and brainstem were normal.     

Adult-onset neurodegeneration with brain iron accumulation and cortical alpha-synuclein and tau pathology: a distinct clinicopathological entity

BACKGROUND: Neurodegeneration with brain iron accumulation is a rare neurodegenerative disorder characterized by iron deposition in the basal ganglia and neuroaxonal dystrophy. Familial cases with mutations in the pantothenate kinase gene are associated with a specific phenotype. In contrast, sporadic cases are heterogeneous in their clinical presentation. OBJECTIVE: To describe an atypical case of sporadic late-onset neurodegeneration with brain iron accumulation. DESIGN, SETTING, AND PATIENT: Case report of a patient who presented with psychiatric features at age 22 years followed by progressive gait disturbance, extrapyramidal symptoms, epilepsy, and corticospinal tract involvement. RESULTS: Magnetic resonance imaging showed iron deposition in the globus pallidus and substantia nigra. Cortical biopsy revealed Lewy bodies with predominant alpha-synuclein and less extensive tau-positive neurites. CONCLUSIONS: Our findings in association with previously reported cases suggest that cortical neuritic and Lewy body pathology is a feature of atypical neurodegeneration with brain iron accumulation, clinically characterized by adult onset and psychiatric symptoms. These observations raise the possibility that these cases of atypical neurodegeneration with brain iron accumulation represent a distinct clinicopathological syndrome and suggest a molecular link between iron deposition and alpha-synuclein accumulation.     

Mitochondrial protein associated neurodegeneration – Case report

Neurodegeneration with brain iron accumulation (NBIA) is a group of genetic disorders with a progressive extrapyramidal syndrome and excessive iron deposition in the brain, particularly in the globus pallidus and substantia nigra. We present the case of a 31-year-old woman with mitochondrial protein associated neurodegeneration (MPAN). MPAN is a new identified subtype of NBIA, caused by mutations in C19orf12 gene. The typical features are speech and gait disturbances, dystonia, parkinsonism and pyramidal signs. Common are psychiatric symptoms such as impulsive or compulsive behavior, depression and emotional lability. In almost all cases, the optic atrophy has been noted and about 50% of cases have had a motor axonal neuropathy. In the MRI on T2- and T2*-weighted images, there are hypointense lesions in the globus palidus and substantia nigra corresponding to iron accumulation.     

DRPLA: An unusual disease or an underestimated cause of ataxia in Brazil?

BackgroundDentatorubral-pallidoluysian atrophy (DRPLA) is a rare autosomal dominant spinocerebellar ataxia caused by pathological expansion of CAG trinucleotide repeats in the ATN1 gene. Most cases were described in patients from Japanese ancestry who presented with adult-onset progressive cerebellar ataxia associated with cognitive impairment, choreoathetosis and other movement disorders. DRPLA has been rarely described in Brazilian patients.MethodsWe performed a retrospective observational multicentric study including six different Neurology Centers in Brazil. All patients with genetically confirmed diagnosis of DRPLA had their medical records evaluated and clinical, genetic and neuroimaging features were analyzed.ResultsWe describe of eight Brazilian patients (5 male, 3 female) from four nuclear families with genetically confirmed DRPLA. The most common neurological features included cerebellar ataxia (n = 7), dementia (n = 3), chorea (n = 2), psychiatric disturbances (n = 2), progressive myoclonic epilepsy (n = 2) and severe bulbar signs (n = 1). Progressive myoclonic epilepsy was observed in two juvenile-onset cases before 20-year. A large CAG trinucleotide length was observed in the two juvenile-onset cases and genetic anticipation was observed in all cases. Neuroimaging studies disclosed cerebellar atrophy (n = 6), as well as brainstem and cerebellar atrophy (n = 2) and leukoencephalopathy (n = 1).ConclusionThe patients described herein reinforce that clinical features of DRPLA are highly influenced by age of onset, genetic anticipation and CAG repetition lengths. There is a large complex spectrum of neurological features associated with DRPLA, varying from pure cerebellar ataxia to dementia associated with other movement disorders (myoclonus, choreoathetosis). DRPLA is an unusual cause of cerebellar ataxia and neurodegeneration in Brazilian patients.