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Initial Cerebellar Ataxia in Hereditary Adult-Onset Primary Lateral Sclerosis.

ABSTRACT: Cerebellar ataxia preceding the apparition of primary lateral sclerosis (PLS) is reported herein. Three individuals from 2 independent kindreds experienced ataxia before developing clinical signs of PLS. Disease onset was during the sixth decade or later, and an insidious onset, with progression exceeding 11 years, was observed. Pathochrony was homogenous, consisting of initial gait instability, followed by hand dysmetria 2 years later. During a 5-year follow-up, cerebellar ataxia remained the sole clinical manifestation, preceding the appearance of muscle stiffness, which progressed to a paraparesis, and then to a purely spastic quadriparesis, over 4 years; pseudobulbar dysarthria and dysphagia appeared later. At this disease stage, limb spasticity, hyperactive jaw and limb stretch reflexes, extensor plantar responses, and a spastic dysarthria were found on examination; limb dysmetria and an ataxo-spastic gait were also found. No muscle atrophy or fasciculation was observed. Among ancillary tests, electromyographic studies performed 6 years after disease onset revealed normal motor unit action potentials and absence of spontaneous activity, in 2 individuals. MRI revealed normal cerebellum and brainstem in 2 cases. Inheritance was dominant in both kindreds, and extensive genetic testing was negative. It is concluded that cerebellar ataxia preceded the appearance of a purely spastic spinobulbar syndrome (which fulfilled the clinical diagnostic criteria for PLS) during a 5-year period in 3 patients with a hereditary, adult-onset form of PLS; subsequent disease progression was equivalent to that of sporadic PLS. Further studies are needed to fully delineate the clinical and genetic spectra of adult-onset PLS.

SUBMITTER: Gazulla J

PROVIDER: S-EPMC8299400 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Clinicoanatomic correlation in the spinocerebellar ataxias (SCA) and Friedreich's ataxia (FRDA) is difficult as these diseases differentially affect multiple sites in the central and peripheral nervous systems. A new way to study cerebellar ataxia is the systematic analysis of the "reciprocal cerebellar circuitry" that consists of tightly organized reciprocal connections between Purkinje cells, dentate nuclei (DN), and inferior olivary nuclei (ION). This circuitry is similar to but not identical with the "cerebellar module" in experimental animals. Neurohumoral transmitters operating in the circuitry are both inhibitory (γ-aminobutyric acid in corticonuclear and dentato-olivary fibers) and excitatory (glutamate in olivocerebellar or climbing fibers). Glutamatergic climbing fibers also issue collaterals to the DN. The present study applied five immunohistochemical markers in six types of SCA (1, 2, 3, 6, 7, 17), genetically undefined SCA, FRDA, and FRDA carriers to identify interruptions within the circuitry: calbindin-D28k, neuron-specific enolase, glutamic acid decarboxylase, and vesicular glutamate transporters 1 and 2. Lesions of the cerebellar cortex, DN, and ION were scored according to a guide as 0 (normal), 1 (mild), 2 (moderate), and 3 (severe). Results of each of the five immunohistochemical stains were examined separately for each of the three regions. Combining scores of each anatomical region and each stain yielded a total score as an indicator of pathological severity. Total scores ranged from 16 to 38 in SCA-1 (nine cases); 22 to 39 in SCA-2 (six cases); 9 to 15 in SCA-3 (four cases); and 13 and 25 in SCA-6 (two cases). In single cases of SCA-7 and SCA-17, scores were 16 and 31, respectively. In two genetically undefined SCA, scores were 36 and 37, respectively. In nine cases of FRDA, total scores ranged from 11 to 19. The low scores in SCA-3 and FRDA reflect selective atrophy of the DN. The FRDA carriers did not differ from normal controls. These observations offer a semiquantitative assessment of the critical role of the DN in the ataxic phenotype of SCA and FRDA while other parts of the circuitry appear less important.

Project description:BackgroundCoding and noncoding repeat expansions are an important cause of neurodegenerative diseases.ObjectiveThis study determined the clinical and genetic features of a large German family that has been followed for almost 2 decades with an autosomal dominantly inherited spinocerebellar ataxia (SCA) and independent co-occurrence of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).MethodsWe carried out clinical examinations and telephone interviews, reviewed medical records, and performed magnetic resonance imaging and positron emission tomography scans of all available family members. Comprehensive genetic investigations included linkage analysis, short-read genome sequencing, long-read sequencing, repeat-primed polymerase chain reaction, and Southern blotting.ResultsThe family comprises 118 members across seven generations, 30 of whom were definitely and five possibly affected. In this family, two different pathogenic mutations were found, a heterozygous repeat expansion in C9ORF72 in four patients with ALS/FTD and a heterozygous repeat expansion in DAB1 in at least nine patients with SCA, leading to a diagnosis of DAB1-related ataxia (ATX-DAB1; SCA37). One patient was affected by ALS and SCA and carried both repeat expansions. The repeat in DAB1 had the same configuration but was larger than those previously described ([ATTTT]≈75 [ATTTC]≈40-100 [ATTTT]≈415 ). Clinical features in patients with SCA included spinocerebellar symptoms, sometimes accompanied by additional ophthalmoplegia, vertical nystagmus, tremor, sensory deficits, and dystonia. After several decades, some of these patients suffered from cognitive decline and one from additional nonprogressive lower motor neuron affection.ConclusionWe demonstrate genetic and clinical findings during an 18-year period in a unique family carrying two different pathogenic repeat expansions, providing novel insights into their genotypic and phenotypic spectrums. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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Initial Cerebellar Ataxia in Hereditary Adult-Onset Primary Lateral Sclerosis.

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