Franziska Hoche

Degeneration of the Cerebellum in Huntington's Disease (HD): Possible Relevance for the Clinical Picture and Potential Gateway to Pathological Mechanisms of the Disease Process

Huntingtons disease (HD) is a polyglutamine disease and characterized neuropathologically by degeneration of the striatum and select layers of the neo‐ and allocortex. In the present study, we performed a systematic investigation of the cerebellum in eight clinically diagnosed and genetically confirmed HD patients. The cerebellum of all HD patients showed a considerable atrophy, as well as a consistent loss of Purkinje cells and nerve cells of the fastigial, globose, emboliform and dentate nuclei. This pathology was obvious already in HD brains assigned Vonsattel grade 2 striatal atrophy and did not correlate with the extent and distribution of striatal atrophy. Therefore, our findings suggest (i) that the cerebellum degenerates early during HD and independently from the striatal atrophy and (ii) that the onset of the pathological process of HD is multifocal. Degeneration of the cerebellum might contribute significantly to poorly understood symptoms occurring in HD such as impaired rapid alternating movements and fine motor skills, dysarthria, ataxia and postural instability, gait and stance imbalance, broad‐based gait and stance, while the morphological alterations (ie ballooned neurons, torpedo‐like axonal inclusions) observed in the majority of surviving nerve cells may represent a gateway to the unknown mechanisms of the pathological process of HD.

Neurodegeneration in ataxia telangiectasia: what is new? What is evident?

This article summarizes evident and recent findings on the characteristics of the neurological phenotype in ataxia telangiectasia (AT), reviews neuropathological and neuroradiological findings, and outlines therapeutic treatment options. In addition, this review offers an overview of current hypotheses on mechanisms of neurodegeneration in AT and discusses their relevance in clinical neurology. The obvious features of neurodegeneration in AT-cerebellar ataxia and dysarthia-are accompanied by a variety of further disabling disease symptoms. Review of the literature outlines a complex pattern of central nervous degeneration in AT that might have been underestimated so far. Neurodegeneration in AT is closely related to the absence or partial lack of the ataxia telangiectasia-mutated (ATM) kinase. ATM is a central player in maintaining cellular homeostasis. Systemic review of the literature reveals a subset of cellular targets hypothesized to count responsible for degeneration in ATM-deficient neurons. Further systematic cliniconeurological, pathoanatomical, and neuroradiological studies are required to understand the structural basis of this neurodegenerative disease. This better understanding has implications for the treatment of AT patients. Second, biochemical and molecular biological studies aimed at deciphering the pathomechanisms of this progressive disorder are necessary for the development of promising future therapies.

Involvement of the auditory brainstem system in spinocerebellar ataxia type 2 (SCA2), type 3 (SCA3) and type 7 (SCA7)

Aims: The spinocerebellar ataxia type 2 (SCA2), type 3 (SCA3) and type 7 (SCA7) are clinically characterized by progressive and severe ataxic symptoms, dysarthria, dysphagia, oculomotor impairments, pyramidal and extrapyramidal manifestations and sensory deficits. Although recent clinical studies reported additional disease signs suggesting involvement of the brainstem auditory system, this has never been studied in detail in SCA2, SCA3 or SCA7. Methods: We performed a detailed pathoanatomical investigation of unconventionally thick tissue sections through the auditory brainstem nuclei (that is, nucleus of the inferior colliculus, nuclei of the lateral lemniscus, superior olive, cochlear nuclei) and auditory brainstem fibre tracts (that is, lateral lemniscus, trapezoid body, dorsal acoustic stria, cochlear portion of the vestibulocochlear nerve) of clinically diagnosed and genetically confirmed SCA2, SCA3 and SCA7 patients. Results: Examination of unconventionally thick serial brainstem sections stained for lipofuscin pigment and Nissl material revealed a consistent and widespread involvement of the auditory brainstem nuclei in the SCA2, SCA3 and SCA7 patients studied. Serial brainstem tissue sections stained for myelin showed loss of myelinated fibres in two of the auditory brainstem fibre tracts (that is, lateral lemniscus, trapezoid body) in a subset of patients. Conclusions: The involvement of the auditory brainstem system offers plausible explanations for the auditory impairments detected in some of our and other SCA2, SCA3 and SCA7 patients upon bedside examination or neurophysiological investigation. However, further clinical studies are required to resolve the striking discrepancy between the consistent involvement of the brainstem auditory system observed in this study and the comparatively low frequency of reported auditory impairments in SCA2, SCA3 and SCA7 patients.

Involvement of the cholinergic basal forebrain nuclei in spinocerebellar ataxia type 2 (SCA2)

Spinocerebellar ataxia type 2 (SCA2) belongs to the CAG repeat or polyglutamine diseases. Along with a large variety of motor, behavioural and neuropsychological symptoms the clinical picture of patients suffering from this autosomal dominantly inherited ataxia may also include deficits of attention, impairments of memory, as well as frontal‐executive and visuospatial dysfunctions. As the possible morphological correlates of these cognitive SCA2 deficits are unclear we examined the cholinergic basal forebrain nuclei, which are believed to be crucial for several aspects of normal cognition and may contribute to impairments of cognitive functions under pathological conditions.

Novel N-terminal truncating CLCN1 mutation in severe Becker disease.

Myotonia congenita (MC) is a nondystrophic muscle disorder resulting from mutation of the skeletal muscle chloride channel 1 (CLCN1) gene on chromosome 7q35, which codes for muscle chloride channel 1 (CIC-1). CIC-1 contributes 80% of the resting membrane conductance of skeletal muscle, so dysfunction results in delayed skeletal muscle relaxation after voluntary contraction. ClC-1 is a “double-barreled” homodimer with 4 proposed sites of dimerization. Each allelic gene product is thought to contribute to its own pore. CLCN1 mutations have a wide range of inheritance patterns, including autosomal dominant (AD), autosomal dominant with reduced penetrance, and autosomal recessive (AR). Early truncating (i.e., nonsense) mutations are thought to have AR inheritance due to loss of the ability of allelic gene products to produce heterodimers. We clinically, electrophysiologically, and genetically investigated a 15-year-old boy of German/Indian nonconsanguineous descent. The patient had symptoms of severe MC. He presented with a history of clumsy and stiff gait from age 10 years, myotonia after rapid initiation of movements, post-myotonic weakness, muscle pain, caudal-cranial progression of involvement of myotonic muscle groups, and aggravation of symptoms with cold temperature. Clinical features included lid, percussion, handgrip, and masticatory myotonia, toe-walking, and compensatory lordosis. A conclusion regarding degree of muscle hypertrophy or atrophy could not be made due to class 1 obesity (body mass index 31.1) (Fig. 1a and b). Electroencephalogram, electrocardiogram, creatine kinase, and motor nerve conduction studies of fibular and tibial nerves bilaterally were normal; molecular analysis revealed a novel compound heterozygous Dc.53-65 (S18Tfs*55) mutation in exon 1 of the CLCN1 gene (Fig. 1d and e) and a previously noted c.1453 A>G (M485V) recessive mutation in exon 13. Both parents were heterozygous carriers of the mutations and were unaffected clinically. The father carried the S18Tfs*55 mutation. There were no siblings. Electromyographic examination (EMG) of the patient’s right vastus medialis (VM) and abductor pollicis brevis (APB) muscles showed substantial spontaneous activity and prominent myotonic discharges on short exercise test (SET) and long exercise test (LET) (Fig. 1c). EMG of the father was not available. Pharmacological management was indicated, as the patient’s quality of life deteriorated. As mexiletine is not available in Germany, intervention with gabapentin (GBT) was initiated. GBT caused major side effects and provided no symptom relief. Second-line treatment with carbamazepine (CBZ) was tolerated well with no side effects. Full symptom relief was achieved at a dose of 16.4 mg/kg/day with a serum CBZ level of 8.4 mg/ml. After 2 years of treatment, the patient reached a normal body weight and reported a substantial improvement in quality of life. Early truncating mutations, such as S18Tfs*55, lead to a degraded CLCN1 transcript that precludes dimerization and results in CLCN1-encoded chloride channels produced by the parental allele, in this case containing the recessive M485V mutation. Phenotypic variability of this novel mutation should be investigated in larger families with the same mutation. Results of pharmacologic intervention suggest that CBZ may represent a potent anti-myotonic treatment in patients with severe myotonia and early truncating mutations.

Description of a novel c.374 G>A mutation in becker disease

Myotonia congenita (MC) is a non-dystrophic muscle disorder that can be inherited in an autosomal dominant (AD; Thomsen disease; OMIM #160800) or autosomal recessive (AR; Becker disease; OMIM #255700) manner. Both forms of MC result from mutations in the skeletal muscle chloride channel 1 (CLCN1) gene on chromosome 7q35 that codes for the muscle chloride channel 1 (ClC-1). ClC-1 contributes up to 80% of the resting membrane conductance of skeletal muscle cells. CLCN1 mutations lead to a significant reduction in resting membrane conductance. Hence, the clinical hallmark in both diseases is delayed skeletal muscle relaxation after voluntary contraction or mechanical stimulation, called myotonia. Becker and Thomsen disease differ in their phenotypic presentation, but mutations causing both forms of the disease have been described throughout the CLCN1 coding region. We performed clinical and genetic investigation of a 9-year-old Turkish girl who was the daughter of consanguineous parents (Fig. 1a and b) and presented with symptoms of recessive MC. We also performed genotype and electrophysiologic analyses on her parents. The 7year-old brother of the patient was unaffected clinically. The patient presented with a history of clumsy and stiff gait since 3 years of age. She had no aggravation of symptoms with cold temperature, but reported a warmup phenomenon. The father reported that he had mild grip myotonia, which was not observable upon clinical examination. The mother had no history or symptoms of myotonia. Neurologic examination of the patient revealed generalized muscle hypertrophy, mild grip myotonia, percussion myotonia of the deltoid and thenar muscles, and weakness after rest in the upper extremities. Molecular analysis was approved by our local ethics committee for the patient and her parents, but not the brother. The analysis revealed a novel AR homozygous c.374G>A (Gly-125-Glu) missense mutation in exon 3 of the CLCN1 gene of the patient. Both parents are heterozygous carriers of the same mutation. Electrophysiologic assessment of the father showed normal results on the short exercise test (SET) and the long exercise test (LET), and there were no myotonic discharges or abnormal spontaneous activity on EMG. Medical treatment for myotonia was refused by the patient and her parents, as the symptoms did not significantly affect her daily life activities. To date, more than 100 mutations are known in CLCN1, and novel mutations are frequently detected. The majority of these alterations are missense mutations that can present with either recessive or dominant inheritance and sometimes may not be clearly distinguished due to reduced penetrance or lower clinical expressivity in females. The novel AR homozygous c.374G>A (Gly125-Glu) missense mutation reported here did not present with clinical or electrophysiologically verifiable latent myotonia in the father. Based on these data, we hypothesize that heterozygous carriers of this novel mutation preserve the critical threshold to maintain regular chloride membrane conductance. This may indicate that the mutation leads to the classical non-dystrophic phenotype of autosomal recessive Becker disease most likely to: (1) reach its full gene-dose effect at a homozygous carrier level; and (2) not present with dominant mutational genetic features in this particular family.