MRI CNS Atrophy Pattern and the Etiologies of Progressive Ataxias

MRI shows in-vivo the three archetypal patterns of CNS volume loss underlying progressive ataxias, 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 Freidreich’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. The MRI-based CNS atrophy pattern may be useful for genetic assessment, identification of shared cellular targets, and repurposing therapies or enlargement of drugs indications in progressive ataxias.

Cerebellar Disorders and Ataxias: Inherited Disorders

Disorders of the cerebellum or its circuitry can result in ataxia. These disorders may be acquired or inherited. Inherited ataxias may be autosomal recessive (eg. Friedrich ataxia), autosomal dominant (eg, spinal cerebellar atrophy) or X linked (eg, fragile X–associated ataxia syndrome). Chapter 73 (“Cerebellar Disorders and Ataxias: Acquired Disorders”) reviews the clinical approach to patients with ataxia and discusses acquired forms of ataxia. This chapter reviews clinical approaches, diagnostic details, and treatment of inherited ataxias.

MTSS1/Src family kinase dysregulation underlies multiple inherited ataxias

The genetically heterogeneous spinocerebellar ataxias (SCAs) are caused by Purkinje neuron dysfunction and degeneration, but their underlying pathological mechanisms remain elusive. The Src family of nonreceptor tyrosine kinases (SFK) are essential for nervous system homeostasis and are increasingly implicated in degenerative disease. Here we reveal that the SFK suppressor Missing-in-metastasis (MTSS1) is an ataxia locus that links multiple SCAs. MTSS1 loss results in increased SFK activity, reduced Purkinje neuron arborization, and low basal firing rates, followed by cell death. Surprisingly, mouse models for SCA1, SCA2, and SCA5 show elevated SFK activity, with SCA1 and SCA2 displaying dramatically reduced MTSS1 protein levels through reduced gene expression and protein translation, respectively. Treatment of each SCA model with a clinically approved Src inhibitor corrects Purkinje neuron basal firing and delays ataxia progression in MTSS1 mutants. Our results identify a common SCA therapeutic target and demonstrate a key role for MTSS1/SFK in Purkinje neuron survival and ataxia progression.

Ataxias

Autosomal recessive cerebellar ataxias are a group of inherited neurological disorders with progressive balance and gait difficulties. In these disorders, cerebellar ataxia is often accompanied by eye movement abnormalities and peripheral nervous system involvement. A unifying mechanism for disease pathogenesis that is common to all the recessive ataxias likely does not exist. Nevertheless, some pathophysiological pathways are common to several autosomal recessive cerebellar ataxias. Specific gene defects in each disorder are summarized in the chapter. The most common recessively inherited ataxias are Friedreich ataxia and Ataxia telangiectasia. A recessive ataxia must be considered for any individual with progressive cerebellar ataxia with onset less than 30 years. The treatment is primarily supportive, but some recessive ataxias have specific treatment.

Cerebellar Ataxia

This chapter deals with disorders of the cerebellum and its connections. These conditions may be identified by the mode of onset—whether acute, subacute, chronic, or episodic. The chronic ataxias are inherited in various patterns: autosomal dominant; autosomal recessive; X-linked. Autosomal dominant inherited ataxias discussed include spinocerebellar ataxia, autosomal dominant episodic ataxia, and glucose transporter type I deficiency syndrome. Some episodic ataxias have variable inheritance. Other episodic ataxias without a clear genetic basis are detailed including mitochondrial spinocerebellar ataxia and epilepsy; coenzyme Q deficiency; progressive cerebellar ataxia with palatal tremor; and progressive cerebellar gait ataxia, myoclonic epilepsy, and intention tremor. Also various disorders associated with ataxia are enumerated.

Ataxias

This chapter explores the historical development of understanding about the structure, function, and disorders of the cerebellum. The chosen papers represent the following development: the discovery that the cerebellum is concerned with movement control rather than movement generation; the first recognition of a distinct spinocerebellar disorder; recognition of the existence of dominantly-inherited ataxias; the delineation of the classic motor features of ataxia; the formal recognition of paraneoplastic cerebellar degenerations; the description of truncal ataxia due to anterior vermal damage in chronic alcoholics; the demonstration of long-term depression at the parallel fibre; the discovery of the first gene (ATXN 1) for a dominantly-inherited spinocerebellar ataxia; the revelation that episodic ataxia type 2 is an ion channel disorder; and the recognition of a cerebellar role in cognition and emotional regulation.