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Am J Hum Genet 2022 May 6;109(5):909-927. Epub 2022 Apr 6.

Université Paris Cité, Developmental Brain Disorders Laboratory, Imagine Institute, INSERM UMR 1163, Paris 75015, France. Electronic address:

Pontocerebellar hypoplasias (PCHs) are congenital disorders characterized by hypoplasia or early atrophy of the cerebellum and brainstem, leading to a very limited motor and cognitive development. Although over 20 genes have been shown to be mutated in PCHs, a large proportion of affected individuals remains undiagnosed. We describe four families with children presenting with severe neonatal brainstem dysfunction and pronounced deficits in cognitive and motor development associated with four different bi-allelic mutations in PRDM13, including homozygous truncating variants in the most severely affected individuals. Read More

Biomedicines 2022 Mar 3;10(3). Epub 2022 Mar 3.

Institute of Clinical Neurobiology, Alberichgasse 5/13, A-1150 Vienna, Austria.

Multiple system atrophy (MSA) is a fatal, rapidly progressing neurodegenerative disease of uncertain etiology, clinically characterized by various combinations of Levodopa unresponsive parkinsonism, cerebellar, autonomic and motor dysfunctions. The morphological hallmark of this α-synucleinopathy is the deposition of aberrant α-synuclein in both glia, mainly oligodendroglia (glial cytoplasmic inclusions /GCIs/) and neurons, associated with glioneuronal degeneration of the striatonigral, olivopontocerebellar and many other neuronal systems. Typical phenotypes are MSA with predominant parkinsonism (MSA-P) and a cerebellar variant (MSA-C) with olivocerebellar atrophy. Read More

Tomography 2022 02 8;8(1):423-437. Epub 2022 Feb 8.

Department of Clinical and Experimental Biomedical Sciences "Mario Serio", University of Florence, Viale GB Morgagni 50, 50134 Florence, Italy.

MRI shows the three archetypal patterns of CNS volume loss underlying progressive ataxias in vivo, namely spinal atrophy (SA), cortical cerebellar atrophy (CCA) and olivopontocerebellar atrophy (OPCA). The MRI-based CNS atrophy pattern was reviewed in 128 progressive ataxias. A CNS atrophy pattern was identified in 91 conditions: SA in Friedreich's ataxia, CCA in 5 acquired and 72 (24 dominant, 47 recessive,1 X-linked) inherited ataxias, OPCA in Multi-System Atrophy and 12 (9 dominant, 2 recessive,1 X-linked) inherited ataxias. Read More

Arch Argent Pediatr 2022 02 1;120(1):e39-e48. Epub 2022 Jan 1.

Facultad de Medicina, Universidad de La Sabana, Bogotá, Colombia.

The latest method of next-generation sequencing has allowed the characterization and identification of genetic variants associated to diverse pathologies. In this article, we present the case of female patient with a mutation of the RARS2 gene that encodes the enzyme for arginyl tRNA synthetase for coding of proteins. This genetic alteration manifests in pontocerebellar hypoplasia type 6, with a prevalence of<1/1,000,0000, characterized by a cerebellum and pons that are smaller in size and are associated with severe neurodevelopmental delay. Read More

Am J Case Rep 2021 Dec 21;22:e934417. Epub 2021 Dec 21.

Department of Pediatrics, University of Tsukuba Hospital, Tsukuba, Ibaraki, Japan.

BACKGROUND The interference of biotin administration with thyroid function tests has been reported; however, it remains unclear in clinical practice. In this report, we present the case of a neonate with a diagnosis of pontocerebellar hypoplasia type 6 (PCH6) treated with biotin who developed biotin interference with laboratory thyroid function tests. CASE REPORT A 1-day-old male infant with hypothermia, tachypnea, and lactic acidosis had a suspected diagnosis of mitochondrial disease. Read More

Cerebellum 2021 Nov 3. Epub 2021 Nov 3.

Service of Neurology, University Hospital "Marqués de Valdecilla (IDIVAL)", University of Cantabria, and "Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED)", Santander, Spain.

The aim of this paper is to carry out a historical overview of the evolution of the knowledge on degenerative cerebellar disorders and hereditary spastic paraplegias, over the last century and a half. Original descriptions of the main pathological subtypes, including Friedreich's ataxia, hereditary spastic paraplegia, olivopontocerebellar atrophy and cortical cerebellar atrophy, are revised. Special attention is given to the first accurate description of striatonigral degeneration by Hans Joachim Scherer, his personal and scientific trajectory being clarified. Read More

J Neural Transm (Vienna) 2021 10 6;128(10):1507-1527. Epub 2021 Oct 6.

ASU-Banner Neurodegenerative Disease Research Center, Biodesign Institute, Arizona State University, Tempe, AZ, USA.

Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by striatonigral degeneration (SND), olivopontocerebellar atrophy (OPCA), and dysautonomia with cerebellar ataxia or parkinsonian motor features. Isolated autonomic dysfunction with predominant genitourinary dysfunction and orthostatic hypotension and REM sleep behavior disorder are common characteristics of a prodromal phase, which may occur years prior to motor-symptom onset. MSA is a unique synucleinopathy, in which alpha-synuclein (aSyn) accumulates and forms insoluble inclusions in the cytoplasm of oligodendrocytes, termed glial cytoplasmic inclusions (GCIs). Read More

J Neural Transm (Vienna) 2021 Oct 28;128(10):1481-1494. Epub 2021 Jul 28.

Department of Neurology, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria.

Multiple System Atrophy (MSA) is a rare, fatal neurodegenerative disorder. Its etiology and exact pathogenesis still remain poorly understood and currently no disease-modifying therapy is available to halt or slow down this detrimental neurodegenerative process. Hallmarks of the disease are α-synuclein rich glial cytoplasmic inclusions (GCIs). Read More

Brain Pathol 2022 01 13;32(1):e13002. Epub 2021 Jul 13.

Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University, Nagakute, Japan.

The striatonigral and olivopontocerebellar systems are known to be vulnerable in multiple system atrophy (MSA), showing neuronal loss, astrogliosis, and alpha-synuclein-immunoreactive inclusions. MSA patients who displayed abundant neuronal cytoplasmic inclusions (NCIs) in the regions other than the striatonigral or olivopontocerebellar system have occasionally been diagnosed with variants of MSA. In this study, we report clinical and pathologic findings of MSA patients characterized by prominent pathologic involvement of the hippocampus. Read More

Neuropediatrics 2021 12 12;52(6):495-498. Epub 2021 Jul 12.

Department of Pediatrics and Adolescent Medicine, Center for Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Introduction: Pontocerebellar hypoplasia type 2 (PCH2) is a rare neurodevelopmental disease with a high disease burden. Besides neurological symptoms, somatic symptoms, such as gastroesophageal reflux (GERD) and failure to thrive, are major contributors to this burden.

Methods: We report three patients with genetically confirmed PCH2A and significant gastrointestinal (GI) symptoms. Read More

Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2021 Jul;38(7):667-670

Department of Gynecology and Obstetrics, Huaian Maternal and Child Health Care Hospital, Huaian, Jiangsu 223002, China.

Objective: To explore the genetic basis for a fetus with cerebellar dysplasia and widened lateral ventricles.

Methods: The couple have elected induced abortion after careful counseling. Skin tissue sample from the abortus and peripheral venous blood samples from both parents were collected for the extraction of genomic DNA, which was then subjected to whole exome sequencing. Read More

Mov Disord 2021 11 8;36(11):2605-2614. Epub 2021 Jul 8.

Laboratory for Translational Neurodegeneration Research, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.

Background: Multiple system atrophy (MSA) is a fatal neurodegenerative disorder characterized by aggregated α-synuclein (α-syn) in oligodendrocytes and accompanied by striatonigral and olivopontocerebellar degeneration and motor symptoms. Key features of MSA are replicated in the PLP-α-syn transgenic mouse, including progressive striatonigral degeneration and motor deterioration. There are currently no approved treatments for MSA. Read More

Neuromuscul Disord 2021 08 28;31(8):773-782. Epub 2021 May 28.

Grupo de Enfermedades Raras, Mitocondriales y Neuromusculares (ERMN). Instituto de Investigación Hospital 12 de Octubre (i+12), E-28041 Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), U723, E-28041 Madrid, Spain. Electronic address:

We report the case of a 16-year-old Spanish boy with cerebellar and spinal muscular atrophy, spasticity, psychomotor retardation, nystagmus, ophthalmoparesis, epilepsy, and mitochondrial respiratory chain (MRC) deficiency. Whole exome sequencing (WES) uncovered three variants (two of them novel) in a compound heterozygous in EXOSC8 gene (NM_181503.3:c. Read More

J Pak Med Assoc 2021 Apr;71(4):1252-1254

Department of Rehabilitation Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Hypertrophic olivary degeneration is a kind of trans-synaptic degeneration, caused by the interruption of dentato rubro olivary pathway. Magnetic resonance imaging (MRI) has been the best modality to show the signals of olivary nucleus hypertrophy. It appears on T2-weighted magnetic resonance imaging as hyper-intensities. Read More

J Med Genet 2022 04 5;59(4):399-409. Epub 2021 Mar 5.

Unit of Neuromuscular and Neurodegenerative Diseases, Department of Neuroscience and Neurorehabilitation, IRCCS Bambino Gesù Children's Hospital, Roma, Italy.

Background: Pontocerebellar hypoplasias (PCH) comprise a group of genetically heterogeneous disorders characterised by concurrent hypoplasia of the pons and the cerebellum and variable clinical and imaging features. The current classification includes 13 subtypes, with ~20 known causative genes. Attempts have been made to delineate the phenotypic spectrum associated to specific PCH genes, yet clinical and neuroradiological features are not consistent across studies, making it difficult to define gene-specific outcomes. Read More

Orphanet J Rare Dis 2021 05 10;16(1):211. Epub 2021 May 10.

Department of Child Neurology, Children's Hospital, University of Tübingen, Hoppe-Seyler-Str. 1, 72072, Tübingen, Germany.

Background: Rare and severe neurological disorders in childhood not only heavily affect the life perspective of the patients, but also their caregivers and families. The aim of this study was to investigate the impact of such diseases on the family, especially on the quality of life and life perspectives of parents, but also on the families' everyday life, based on the model of two diseases which have been well described in recent years with respect to symptoms and course: metachromatic leukodystrophy (MLD) and pontocerebellar hypoplasia type 2 (PCH2). PCH2 is a primary severe developmental disorder, while children with MLD initially develop normally and then progressively deteriorate. Read More

Zhonghua Er Ke Za Zhi 2020 Nov;58(11):893-899

Department of Neurology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China.

To summarize the clinical features of two early onset epileptic encephalopathy (EOEE) patients with arginyl-tRNA synthetase (RARS2) gene variations and to review related literature. The clinical data and genetic features of two pontocerebellar hypoplasia type 6 (PCH6) patients with RARS2 variation diagnosed by the Department of Neurology, Beijing Children's Hospital from January 2017 to December 2018 were analyzed retrospectively. A literature search with "RARS2" "pontocerebellar hypoplasia type 6" and "early onset epileptic encephalopathy" as key words was conducted at China national knowledge infrastructure (CNKI), Wanfang Data Knowledge Service Platform and PubMed (up to May 2020), literature about RARS2 gene variation patients and their complete clinical data were chosen and reviewed. Read More

Neuropediatrics 2021 06 27;52(3):163-169. Epub 2020 Oct 27.

Department of Pediatric Neurology, Academic Medical Center, Amsterdam University Medical Center, Amsterdam, The Netherlands.

Background: Pontocerebellar hypoplasia (PCH) is a rare group of disorders mainly affecting the cerebellum and pons. Supratentorial structures are variably involved. We assessed brain growth patterns in patients with the most frequent forms of PCH, namely PCH1B (OMIM#614678) and PCH2A (OMIM#277470), since in these types of PCH, pre- and postnatal neurodegeneration is established by neuropathological profiling. Read More

Mov Disord 2021 02 27;36(2):449-459. Epub 2020 Oct 27.

Rita Lila Weston Institute, University College London, London, UK.

Background: Multiple system atrophy (MSA) is a rare neurodegenerative disease characterized by intracellular accumulations of α-synuclein and nerve cell loss in striatonigral and olivopontocerebellar structures. Epidemiological and clinical studies have reported potential involvement of autoimmune mechanisms in MSA pathogenesis. However, genetic etiology of this interaction remains unknown. Read More

J Hum Genet 2021 Apr 10;66(4):401-407. Epub 2020 Oct 10.

Department of Human Genetics, Graduate school of medicine, Yokohama City University, Yokohama, Japan.

Pontocerebellar hypoplasia (PCH) is currently classified into 13 subgroups and many gene variants associated with PCH have been identified by next generation sequencing. PCH type 1 is a rare heterogeneous neurodegenerative disorder. The clinical presentation includes early-onset severe developmental delay, progressive motor neuronopathy, and cerebellar and pontine atrophy. Read More

J Neuroimmunol 2020 12 20;349:577395. Epub 2020 Sep 20.

Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Translational Neuroscience Center, Graduate School of Medicine, and School of Pharmacy at Fukuoka, International University of Health and Welfare, 137-1 Enokizu, Ookawa, Fukuoka 831-8501, Japan; Department of Neurology, Brain and Nerve Center, Fukuoka Central Hospital, International University of Health and Welfare, 2-6-11 Yakuin, Chuou-ku, Fukuoka 810-0022, Japan. Electronic address:

To identify biomarkers for multiple system atrophy-cerebellar type (MSA-C), we used flow cytometry to measure surface marker expression of peripheral blood monocytes from patients with MSA-C or hereditary spinocerebellar degeneration (hSCD) and from healthy controls (HCs). The percentage of intermediate monocytes was significantly lower in MSA-C patients than in hSCD patients and HCs and showed significant positive correlations with disease duration and unified MSA rating scale scores. The percentage of CD62L intermediate monocytes was significantly lower in MSA-C patients than in hSCD patients and HCs. Read More

Parkinsonism Relat Disord 2020 11 6;80:1-6. Epub 2020 Sep 6.

Movement Disorders Center, LIM 62, Department of Neurology, School of Medicine, University of São Paulo, São Paulo, Brazil; Service of Interdisciplinary Neuromodulation (SIN), Laboratory of Neurosciences (LIM-27), Department and Institute of Psychiatry, University of São Paulo, São Paulo, Brazil. Electronic address:

Introduction: Cerebellar ataxia remains a neurological symptom orphan of treatment interventions, despite being prevalent and incapacitating. We aimed to study, in a double-blind design, whether cerebellar modulation could improve ataxia.

Methods: We included patients with diagnosis of spinocerebellar ataxia type 3, multiple systems atrophy cerebellar type, or post-lesion ataxia. Read More

Am J Med Genet A 2020 11 1;182(11):2675-2679. Epub 2020 Sep 1.

Struttura Complessa di Neuropsichiatria Infantile, Dipartimento Materno-Infantile, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.

The CAMK2B gene encodes the β-subunit of calcium/calmodulin-dependent protein kinase II (CAMK2), an enzyme that has crucial roles in synaptic plasticity, especially in hippocampal and cerebellar neurons. Heterozygous variants in CAMK2B cause a rare neurodevelopmental disorder, with 40% of the reported cases sharing the same variant: c.416C>T, p. Read More

Genet Mol Biol 2020 08 21;43(3):e20190325. Epub 2020 Aug 21.

Universidad de Guadalajara, Centro Universitario de Ciencias de la Salud - CUCS, Instituto de Genética Humana "Enrique Corona Rivera", Jalisco, Mexico.

The spinocerebellar ataxia type 2 is a neurodegenerative disease with autosomal dominant inheritance; clinically characterized by progressive cerebellar ataxia, slow ocular saccades, nystagmus, ophthalmoplegia, dysarthria, dysphagia, cognitive deterioration, mild dementia, peripheral neuropathy. Infantile onset is a rare presentation that only has been reported in four instances in the literature. In the present work a boy aged 5 years 7 months was studied due to horizontal gaze-evoked nystagmus, without saccades, ataxic gait, dysarthria, dysphagia, dysmetria, generalized spasticity mainly pelvic, bilateral Babinsky. Read More

Am J Med Genet A 2020 10 3;182(10):2377-2383. Epub 2020 Aug 3.

Medical Genetics Unit, Santa Maria della Misericordia Hospital, University of Perugia, Perugia, Italy.

Mutations in the MBOAT7 gene have been described in 43 patients, belonging to 18 families, showing nonspecific clinical features (intellectual disability [ID], seizures, microcephaly or macrocephaly, and mild to moderate cerebellar atrophy) that make the clinical diagnosis difficult. Here we report the first Italian patient, a 22.5-year-old female, one of the oldest reported, born to apparently consanguineous parents. Read More

Clin Nucl Med 2020 Sep;45(9):e419-e421

From the Staten Island University Hospital, Northwell Health, Staten Island, NY.

Olivopontocerebellar atrophy is a rare neurodegenerative syndrome associated with 2 distinct disorders: multiple system atrophy and spinocerebellar ataxia. We present a case involving a 66-year-old man with adult-onset progressing cerebellar signs reflective of a cerebellar syndrome with no significant family history and unremarkable genetic testing for spinocerebellar ataxia. This case was found to be most consistent with sporadic olivopontocerebellar atrophy, which falls under the multiple system atrophy category. Read More

Neuropediatrics 2020 12 6;51(6):440-444. Epub 2020 Jul 6.

Department of Pediatric Neurology and Epilepsy Center, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.

Pontocerebellar hypoplasia (PCH) is an autosomal recessive neurodevelopmental and neurodegenerative disorder characterized by cerebellar and pontine hypoplasia, progressive microcephaly, and developmental delay. Ten types of PCH have been described; PCH type 2A (PCH2A) due to a mutation in is the most frequent. Seizures have been reported in the large majority of patients. Read More

Brain 2020 06;143(6):1798-1810

Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology, 1 Wakefield Street, London WC1N 1PJ, UK.

Recent post-mortem studies reported 22-37% of patients with multiple system atrophy can develop cognitive impairment. With the aim of identifying associations between cognitive impairment including memory impairment and α-synuclein pathology, 148 consecutive patients with pathologically proven multiple system atrophy were reviewed. Among them, 118 (79. Read More

Neurology 2020 05 21;94(19):e2074-e2075. Epub 2020 Apr 21.

From the UOC Neurofisiopatologia (G.P., S.S.), Fondazione Policlinico Universitario A. Gemelli IRCCS; Istituto di Neurologia (G.P., S.S.), Università Cattolica del Sacro Cuore; and Unit of Neuromuscular and Neurodegenerative Disorders (G.Z., M.N.), Department of Neurosciences, IRCCS, Bambino Gesù Research Hospital, Rome, Italy.

Front Neurol 2020 3;11:124. Epub 2020 Mar 3.

Brain Research Center, National Yang-Ming University, Taipei, Taiwan.

Spinocerebellar ataxia type 3 (SCA) is a cerebellum-dominant degenerative disorder that is characterized primarily by infratentorial damage, although less severe supratentorial involvement may contribute to the clinical manifestation. These impairments may result from the efferent loss of the cerebellar cortex and degeneration of the cerebral cortex. We used the three-dimensional fractal dimension (3D-FD) method to quantify the morphological changes in the supratentorial regions and assessed atrophy in the relatively focal regions in patients with SCA3. Read More