Tripeptidyl Peptidase 1 (TPP1) Deficiency in a 36-Year-Old Patient with Cerebellar-Extrapyramidal Syndrome and Dilated Cardiomyopathy

We report on a 36-year-old man with cerebellar-extrapyramidal syndrome and severe heart failure because of dilated cardiomyopathy of unknown origin. Dysarthria and cardiac arrhythmia began at early childhood (4 years of age). Brain MRI (28 years of age) demonstrated severe cerebellar atrophy. At the age 32, he presented with dysarthria, ataxia, dystonia, and tremor of the right hand, bilateral slowed neural conduction in the visual pathways, and decreased mental acuity. At the age of 33 years, the patient underwent cardiac transplantation because of severe dilated cardiomyopathy. In the TPP1 gene, biallelic variants were identified: previously reported p.(Leu13Pro) and novel p.(Tyr508Cys) variant. Additionally, hemizygous novel missense variant in the ABCD1 gene was inherited from the mother p.(Arg17His). Normal very-long-chain fatty acids (VLCFA) levels both in patient and his mother excluded ABCD1 mutation as the pathogenic one. Tripeptidyl peptidase 1 (TPP1) activity was reduced (8,8 U/mg protein/h; reference range: 47.4 ± 10.7). In light microscopy the biopsy specimens obtained from explanted heart showed severe myocyte hypertrophy with perinuclear vacuolization with inclusions. Electron microscopy revealed absence of lipofuscin accumulation, no ultrastructural curvilinear profiles, fingerprint bodies, or granular osmiophilic deposits (GRODs) in lysosomes. As described here, the patient presents clinical symptoms observed in benign forms of ceroid lipofuscinosis type 2 (CLN2) and simultaneously some features of autosomal recessive spinocerebellar ataxia type 7 (SCAR7), which is also caused by mutations in the TPP1 gene.

Involvement of the Auditory Pathway in Spinocerebellar Ataxia Type 7

<b><i>Background:</i></b> Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant disorder caused by a mutation in the <i>ATXN7</i> gene. The involvement of the brainstem auditory pathway in pathogenesis of this disease has not been systematically assessed. <b><i>Aim:</i></b> To determine involvement of the brainstem auditory pathway in SCA7 patients and its relationship to clinical features of the disease. <b><i>Methods:</i></b> In this case-control study, brainstem auditory-evoked potentials (BAEPs) were assessed in 12 SCA7 patients with clinical and molecular diagnosis, compared to 2 control groups of 16 SCA2 patients and 16 healthy controls. <b><i>Results:</i></b> SCA7 patients exhibited significant prolongation of I-wave and III-wave latencies, whereas SCA2 patients showed increased latencies for III and V waves and I–III interpeak interval. SCA7 patients with larger I-wave latencies exhibited larger CAG repeats, earlier onset age, and higher SARA scores, but in SCA2 cases, these were not observed. <b><i>Conclusions:</i></b> BAEP tests revealed functional involvement of the auditory pathway in SCA7 (mainly at) peripheral portions, which gave new insights into the disease physiopathology different from SCA2 and may unravel distinct pathoanatomical effects of polyQ expansions in the central nervous system. <b><i>Significance:</i></b> These findings offer important insights into the distinctive disease mechanisms in SCA7 and SCA2, which could be useful for differential diagnosis and designing specific precision medicine approaches for both conditions.

Respiratory dysfunction in a mouse model of spinocerebellar ataxia type 7

Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant neurodegenerative disorder caused by a CAG repeat expansion in the coding region of the ataxin-7 gene. Infantile-onset SCA7 patients display extremely large repeat expansions (&gt;200 CAGs) and exhibit progressive ataxia, dysarthria, dysphagia and retinal degeneration. Severe hypotonia, aspiration pneumonia and respiratory failure often contribute to death in affected infants. To better understand the features of respiratory and upper airway dysfunction in SCA7, we examined breathing and putative phrenic and hypoglossal neuropathology in a knock-in mouse model of early-onset SCA7 carrying an expanded allele with 266 CAG repeats. Whole-body plethysmography was used to measure awake, spontaneous breathing at baseline in normoxia and during a hypercapnic/hypoxic respiratory challenge at 4 and 8 weeks, before and after onset of disease. Postmortem studies included quantification of putative phrenic and hypoglossal motor neurons and microglia and analysis of ataxin-7 aggregation at end stage. SCA7-266Q mice have profound breathing deficits during a respiratory challenge, exhibiting reduced respiratory output and a greater percentage of time in apnea. Histologically, putative phrenic and hypoglossal motor neurons of SCA7 mice exhibit a reduction in number accompanied by increased microglial activation, indicating neurodegeneration and neuroinflammation. Furthermore, intranuclear ataxin-7 accumulation is observed in cells neighboring putative phrenic and hypoglossal motor neurons in SCA7 mice. These findings reveal the importance of phrenic and hypoglossal motor neuron pathology associated with respiratory failure and upper airway dysfunction, which are observed in infantile-onset SCA7 patients and likely contribute to their early death.

Molecular and electrophysiological features of spinocerebellar ataxia type seven in induced pluripotent stem cells

Spinocerebellar ataxia type 7 (SCA7) is an inherited neurodegenerative disease caused by a polyglutamine repeat expansion in the ATXN7 gene. Patients with this disease suffer from a degeneration of their cerebellar Purkinje neurons and retinal photoreceptors that result in a progressive ataxia and loss of vision. As with many neurodegenerative diseases, studies of pathogenesis have been hindered by a lack of disease-relevant models. To this end, we have generated induced pluripotent stem cells (iPSCs) from a cohort of SCA7 patients in South Africa. First, we differentiated the SCA7 affected iPSCs into neurons which showed evidence of a transcriptional phenotype affecting components of STAGA (ATXN7 and KAT2A) and the heat shock protein pathway (DNAJA1 and HSP70). We then performed electrophysiology on the SCA7 iPSC-derived neurons and found that these cells show features of functional aberrations. Lastly, we were able to differentiate the SCA7 iPSCs into retinal photoreceptors that also showed similar transcriptional aberrations to the SCA7 neurons. Our findings give technical insights on how iPSC-derived neurons and photoreceptors can be derived from SCA7 patients and demonstrate that these cells express molecular and electrophysiological differences that may be indicative of impaired neuronal health. We hope that these findings will contribute towards the ongoing efforts to establish the cell-derived models of neurodegenerative diseases that are needed to develop patient-specific treatments.