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Ataxia is not a common feature in Parkinson's disease. Nevertheless, some rare forms of parkinsonism have ataxia as one of the main features in their clinical picture, especially those with juvenile or early-onset. On the other side, in cerebellar degenerative diseases, parkinsonism might accompany the typical symptoms and even become predominant in some cases. Many disorders involving different neurological systems present with a movement phenomenology reflecting the underlying pattern of pathological involvement, such as neurodegeneration with brain iron accumulation, neurodegeneration associated with calcium deposition, and metabolic and mitochondrial disorders. The prototype of sporadic disorders that present with a constellation of symptoms due to the involvement of multiple Central Nervous System regions is multiple system atrophy, whose motor symptoms at onset can be cerebellar ataxia or parkinsonism. Clinical syndromes encompassing both parkinsonian and cerebellar features might represent a diagnostic challenge for neurologists. Recognizing acquired and potentially treatable causes responsible for complex movement disorders is of paramount importance, since an early diagnosis is essential to prevent permanent consequences. The present review aims to provide a pragmatic overview of the most common diseases characterized by the coexistence of cerebellar and parkinsonism features and suggests a possible diagnostic approach for both inherited and sporadic disorders. This article is part of the Special Issue "Parkinsonism across the spectrum of movement disorders and beyond" edited by Joseph Jankovic, Daniel D. Truong and Matteo Bologna.

Background Neurodegeneration with brain iron accumulation (NBIA) comprises a clinically and genetically heterogeneous group of diseases presenting with movement disorders and brain iron deposits. In addition to NBIA subtypes caused by mutations in PANK2 and PLA2G6, mutations in the C19orf12 gene were recently described as the third frequent cause of NBIA (called mitochondrial membrane protein-associated neurodegeneration, MPAN). Additionally, the X-linked gene WDR45 was found causative for a special subtype named static encephalopathy in childhood with neurodegeneration in adulthood (also called BPAN); however, analysis of this gene in a broader spectrum of NBIA has not been reported yet. Methods In a heterogeneous cohort of 69 patients with suspected NBIA that did not carry mutations in PANK2 and PLA2G6, the coding region of C19orf12 was evaluated by Sanger sequencing. The WDR45 gene was analyzed via high resolution melting and subsequent sequence analysis. Results Previously described homozygous C19orf12 mutations were found in 3/69 NBIA patients (4.3%). Analysis of the WDR45 gene revealed a novel heterozygous missense mutation in one female NBIA patient showing psychomotor retardation with secondary decline. Conclusions C19orf12 mutations were confirmed in our heterogeneous NBIA cohort, while WDR45 mutations appear to be restricted to the subtype showing encephalopathy in childhood with neurodegeneration in adulthood.

Introduction Hereditary Spastic Paraplegia (HSP) represents a complex and heterogeneous group of rare neurodegenerative disorders that share a common clinical feature of weakness and lower limb spasticity that can occur alone or in combination with a constellation of other neurological or systemic signs and symptoms. Although the core clinical feature of weakness and lower limb spasticity is virtually universal, the genetic heterogeneity is almost uncountable with more than 70 genetic forms described so far. We performed review of medical records from twenty-one patients from seventeen Brazilian families with complex phenotype of HSP. All cases have previously negative mutations in SPG11/KIAA1840 and SPG7 gene and were evaluated by whole-exome sequencing. An extensive description of systemic and neurological signs has been described. Results Whole-exome sequencing was unremarkable in eight patients and established a definite genetic diagnosis in thirteen patients of twelve non-related families. Mutations were found in genes previously implicated in other neurodegenerative disorders such as Amyotrophic Lateral Sclerosis, Hereditary Neuropathy, Spastic Ataxias, Neurodegeneration with Brain Iron Accumulation, Glycogen Metabolism, Congenital Lipodystrophy and aminoacyl-tRNA synthetases disorders. Conclusions We report thirteen new genetically-proven cases of complex HSP, expanding the clinical spectrum of presentations of HSP, providing new pathophysiological mechanisms and disclosing new potential therapeutic targets.

Background Mitochondrial membrane protein-associated neurodegeneration (MPAN) is an neurodegeneration with brain iron accumulation (NBIA) subtype with mutation of C19orf12 . Optic atrophy is one of the core symptoms in almost all MPAN cases, but the detailed ophthalmologic features of MPAN patients have not yet been described. Methods All consecutive symptomatic, gene proven MPAN patients underwent a detailed ophthalmological examination: best corrected visual acuity (BCVA), slit lamp examination, dilated fundus examination, tonometry, optical coherent tomography (OCT) and electrophysiological examinations. The total thickness of the macula (Mth) and the retinal nerve fiber layer (RNFL) were measured separately. Results Six males aged 18 to 21 years were examined. Dilated fundus examination revealed complete optic disc paleness in 5 patients. In all patients, the Mth was normal. The total RNFL was thin in five patients. The latencies of PVEP were prolonged in all patients except one. In all cases, the ERG latencies and amplitudes were normal under both scotopic and photopic conditions. One patient, carrying different mutation and with different disease course, had a normal optic nerve head, normal RNFL thickness and PVEP latencies. Conclusions Optic nerve atrophy seems to be genotype-dependent in MPAN patients but is typical for the disease. This phenomenon, together with normal ERG examination, is most distinctive for MPAN.

Objective Behr syndrome, first described in 1909 by the ophthalmologist Carl Behr, is a clinical entity characterised by a progressive optic atrophy, ataxia, pyramidal signs and mental retardation. Some reported cases have been found to carry mutations in the OPA1, OPA3 or C12ORF65 genes which are known causes of pure optic atrophy or optic atrophy complicated by movement disorder. Methods We present the long-term observation of two Turkish sisters with Behr syndrome. We performed neurophysiological, imaging and molecular genetic studies to identify the underlying genetic cause in our patients. Results Magnetic resonance imaging of the brain showed bilateral hypointense signals in the basal ganglia which prompted us to consider neurodegeneration with brain iron accumulation (NBIA) as a differential diagnosis. Molecular genetic studies revealed a homozygous mutation in the C19ORF12 gene which has been previously reported in patients with a subtype of NBIA, mitochondrial membrane protein-associated neurodegeneration (MPAN). Conclusion We expand the spectrum of genetic causes of Behr syndrome. Genetic testing of patients presenting with Behr syndrome should include C19ORF12 mutation screening.

We report a healthy adult male, who underwent, as a control subject, part of a Huntington's disease study, extensive testing during three visits in a two year follow-up, including clinical examination and 3.0 T MRI scans. The T2-weighted MRI sequences revealed the “eye-of-the-tiger-sign”. No clinical abnormalities in either motor, cognitive or behavioural domains were observed. PKAN2 and FTL gene mutation analysis were negative. This finding implies that an eye-of-the-tiger sign, which is considered a pathognomonic feature of neurodegeneration with brain iron accumulation (NBIA), can occur without any clinical symptoms.

Hereditary spastic paraplegia (SPG) is a clinically and genetically heterogeneous group of neurodegenerative disorders that are clinically characterised by progressive spasticity and weakness of the lower-limbs (pure SPG) and, majoritorian, additional more extensive neurological or non-neurological manifestations (complex or complicated SPG). Pure SPG is characterised by progressive spasticity and weakness of the lower-limbs, and occasionally sensory disturbances or bladder dysfunction. Complex SPGs additionally include cognitive impairment, dementia, epilepsy, extrapyramidal disturbances, cerebellar involvement, retinopathy, optic atrophy, deafness, polyneuropathy, or skin lesions in the absence of coexisting disorders. Nineteen SPGs follow an autosomal-dominant (AD-SPG), 27 an autosomal-recessive (AR-SPG), 5 X-linked (XL-SPG), and one a maternal trait of inheritance. SPGs are due to mutations in genes encoding for proteins involved in the maintenance of corticospinal tract neurons. Among the AD-SPGs, 40-45% of patients carry mutations in the SPAST-gene (SPG4) and 10% in the ATL1-gene (SPG3), while the other 9 genes are more rarely involved (NIPA1 (SPG6), KIAA0196 (SPG8), KIF5A (SPG10), RNT2 (SPG12), SPGD1 (SPG13), BSCL2 (SPG17), REEP1 (SPG31), ZFYVE27 (SPG33, debated), and SLC33A1 (SPG42, debated)). Among the AR-SPGs, ~20% of the patients carry mutations in the KIAA1840 (SPG11) gene whereas the 15 other genes are rarely mutated and account for SPGs in single families yet (CYP7B1 (SPG5), SPG7 (SPG7), ZFYVE26 (SPG15), ERLIN2 (SPG18), SPG20 (SPG20), ACP33 (SPG21), KIF1A (SPG30), FA2H (SPG35), NTE (SPG39), GJA12/GJC2 (SPG44), KIAA0415 (SPG48) and 4 genes encoding for the AP4-complex (SPG47)). Among the XL-SPGs, 3 causative genes have been identified (L1CAM (SPG1), PLP1 (SPG2), and SLC16A2 (SPG22)). The diagnosis of SPGs is based on clinical, instrumental and genetic investigations. Treatment is exclusively symptomatic.