Ataxic disorders

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Ataxic disorders

Patients with ataxia show an impairment of coordination in the absence of muscle weakness (Table 29.1). The cause of this relates to one or both of the following:

Table 29.1

Clinical features of ataxia

Core clinical features (variably present according to etiology)

Impaired balance: patients often show a swaying movement of the trunk while standing and have a wide-based stance with a wide-based, often staggering gait

Clumsy limb movements: movements lack proper timing with the trajectory and force being misjudged (dysmetria). On clinical testing there is inability to perform rapidly alternating pronation and supination of the hands (dysdiadochokinesis)There is also poor coordination on the heel–shin test

Tremor: characterized by worsening on movement (intention tremor) seen clinically in the finger–nose test as jerky over-shooting of the finger as it approaches the nose or examiners finger

Dysarthria: often described as scanning speech

Disturbance of eye movements: characterized by nystagmus and jerky pursuit movements on examination

Muscle hypotonia

Associated clinical features (only seen in some cases and may help in establishing a direction for diagnosis)

Impaired proprioception, painful distal neuropathy, pyramidal signs, macrocytic anemia – B12 deficiency

Weight loss, diarrhea, abdominal pain, arthritis – Whipple’s disease

Shooting limb pains, areflexia in the lower limbs, Argyll–Robertson pupils, optic atrophy – syphilis

Early onset, recurrent respiratory tract infections, cutaneous telangiectasia – ataxia telangiectasia

Early onset, sensory neuropathy, pyramidal tract involvement (extensor plantar response), diabetes mellitus, optic atrophy, cardiomyopathy – Friedreich’s ataxia

Pigmented retinal degeneration, parkinsonism, peripheral neuropathy, cognitive decline – hereditary autosomal dominant cerebellar ataxia

Late onset, tremor, cognitive impairment, high signal in the cerebellum on MRI (T2) – FXTAS

Late onset, parkinsonism, autonomic dysfunction – multiple system atrophy (MSA)

Time-course of progression can help with predicting a cause, as follows:

Acute onset of severe ataxia: typically associated with an acquired ataxia caused by a focal pathology (hemorrhage, neoplasm, infarct, demyelination). Drug- and toxin-related acquired ataxias are also possible causes. Less commonly, a patient can present in this manner with an episodic ataxia syndrome

Subacute ataxia becoming progressively worse over several days: typically linked to an acquired ataxia due to an infective, autoimmune, or inflammatory cause including demyelination. Mass lesions in the posterior fossa can also lead to a gradually progressive ataxia

Chronic ataxia with gradual progression over months to years: causes of acquired ataxia would usually have been investigated in such patients, especially toxic causes such as alcohol. Having excluded an acquired etiology, the most important causes to consider are inherited ataxias, metabolic causes, and neurodegenerative disease such as MSA-C or less commonly a prion disease. If all investigations do not establish a cause then a diagnosis of sporadic adult-onset ataxia of unknown etiology (SAOA) is appropriate

Disease of the cerebellum and/or afferent/efferent tracts leading to failure of cerebellar cortical function (cerebellar ataxia).

Disease of peripheral nerves, dorsal root ganglia or ascending tracts in the spinal cord leading to failure of proprioceptive inputs (sensory ataxia).

Patients with ataxia can be considered in three main groups classified according to etiology as follows:

Acquired ataxia: there are many secondary causes of cerebellar disease (i.e. toxic, nutritional, metabolic, inflammatory, infective, ischemic, and paraneoplastic; Table 29.2) and the pathology of these conditions is dealt with in the relevant chapters elsewhere in this book.

Table 29.2

Classification of ataxic disorders

Acquired ataxias

Creutzfeldt–Jakob disease (Chapter 32)

Mass lesion (tumor or abscess)

Toxins and drugs

Ethanol

Anti-epileptic drugs

Lithium

Antibiotics (isoniazid, metronidazole)

Heavy metals (lead, mercury)

Autoimmune disease

Celiac disease

Paraneoplastic syndromes (anti-Hu, anti-Ma, anti-mGluR1, anti-Tr, anti-Rim anti Yo antibodies)

Anti-GQ1b antibodies (Miller Fisher syndrome)

Infections (Whipple’s disease, Epstein–Barr virus, Varicella–Zoster virus, syphilis)

Superficial siderosis

Vitamin deficiency (B12, B1, E)

Thyroid disease

Hereditary ataxias

Autosomal dominant

Spinocerebellar ataxias (SCA1–36)

Dentatorubropallidoluysial atrophy (DRPLA)

Episodic ataxias (linked to mutation in an ion channel)

Familial British dementia and Familial Danish dementia

Autosomal recessive

Friedreich ataxia

Ataxia with selective vitamin E deficiency

Mitochondrial recessive ataxia syndrome (POLG)

DNA repair syndromes (ataxia telangiectasia, xeroderma pigmentosum)

Spinocerebellar ataxia, autosomal recessive) (SCAR 1–10)

Inherited metabolic diseases and congenital disorders

X-linked

Fragile X-associated tremor/ataxia syndrome (FXTAS)

Congenital disorders

Usually recessively inherited pediatric diseases with cerebellar aplasia

Mitochondrial

MERFF, MELAS, NARP

Non-hereditary degenerative ataxias

Multiple system atrophy (MSA-C)

Sporadic adult-onset ataxia of unknown etiology (SAOA)

Hereditary ataxia: conditions with a range of inheritance patterns (Table 29.2).

Non-hereditary neurodegenerative ataxia: degenerative conditions in which a genetic or acquired cause if not evident on investigation (Table 29.2).

This chapter will consider the hereditary and non-hereditary neurodegenerative ataxias. Rapid advances in the characterization of genetic causes in the inherited forms of disease usually allow for testing of patients in life and the establishment of a diagnosis. Those patients with a chronic ataxia in which a genetic or acquired cause cannot be found are classed as having sporadic adult-onset ataxia of unknown etiology (SAOA).

NEUROPATHOLOGICAL CHANGES IN DEGENERATIVE CAUSES OF ATAXIA

While there is significant pathological heterogeneity in the degenerative cerebellar ataxias, some common patterns of pathology are seen. Different causes of degenerative ataxia are associated with specific patterns of disease but there are significant overlaps. No pattern of disease pathology can reliably predict the cause of the ataxia.

Loss of neurons from the cerebellar cortex with associated tract degeneration (cerebellar cortical degeneration) (Fig. 29.1).

29.1 Cerebellar cortical degeneration.
(a) Lateral view of the brain from a patient with pathology of a cerebellar cortical degeneration. Note the marked atrophy of the cerebellum in relation to the size of the cerebrum. (b) Slices through the cerebellar hemispheres and vermis of a control brain (top) and a patient with cerebellar cortical degeneration (bottom). Note the reduction in the volume of cortical gray matter and the widening of the cerebellar sulci in the patient’s cerebellum. (c) Patchy loss of Purkinje cells. (d) Severe diffuse loss of Purkinje cells. There is also marked depletion of granule cells and proliferation of Bergmann astrocytes. (e) The Purkinje cell axonal swellings are readily demonstrable by silver impregnation. (f) Note the ‘empty basket’ to the right of the axonal swelling. (g) Several adjacent ‘empty baskets’ in cerebellar cortical degeneration. (h) The degeneration of Purkinje cells is associated with proliferation of Bergmann astrocytes, at the junction of the granular and molecular layers. Note also the moderate loss of myelinated fibers from the white matter. (i) Bergmann astrocytosis accompanied by isomorphic gliosis of the molecular layer.

Loss of neurons from the cerebellar cortex with associated tract degeneration associated with atrophy and neuronal loss from the inferior olivary nuclei (cerebello-olivary degeneration).

Loss of neurons from the cerebellar cortex, pontine nuclei and inferior olivary nuclei (olivopontocerebellar degeneration) (Fig. 29.2).

29.2 Brain stem in olivopontocerebellar atrophy. The genetic subtype was not determined in this case.
(a,b) This case shows degeneration of the pontine nuclei and transverse pontine fibers. (c) There is moderate depletion of neurons from the inferior olives, and loss of the corresponding afferent and efferent fibers from the amiculum (AO) and hilus (HO), which appear abnormally pale. The hilus of the dentate nucleus (HD) and the superior cerebellar peduncle (SCP) are relatively well preserved.

Loss of myelinated axons from cerebellar afferent projections seen in the cerebellar peduncle, including loss of myelinated axons in tracts in the spinal cord (spinocerebellar degeneration)(Fig. 29.3).

29.3 Friedreich’s ataxia.
(a) There is degeneration of the gracile funiculi and spinocerebellar tracts in the upper cervical cord. As is often the case, at this level the pyramidal tracts are relatively spared. (b) Degeneration of the gracile funiculi. (c) Dense clusters of satellite cells (nodules of Nageotte) mark the sites where dorsal ganglion cells have degenerated. Satellite cells have proliferated to a varying extent around several of the remaining ganglion cells. (d) Marked loss of nerve fibers from a posterior lumbar nerve root.

± Loss of neurons from cerebellar dentate nuclei, cranial nerve nuclei, basal ganglia, substantia nigra, or red nucleus.

± Peripheral neuropathy.

± Systems pathology, e.g. retina, cardiac, skeletal muscle.

CEREBELLAR CORTICAL DEGENERATION

MACROSCOPIC AND MICROSCOPIC APPEARANCES

Cerebellar cortical degeneration is characterized macroscopically by atrophy of the cerebellar folia with widening of the intervening sulci and reduction in the amount of white matter (Fig. 29.1). The histologic changes are non-specific and can be seen in diverse diseases that are clinically, metabolically, or genetically distinct. The Purkinje cells are reduced in number and may be absent from large lengths of cortex (Fig. 29.1c,d). There may also be a loss of granule cells, which is sometimes marked (Fig. 29.1d). Surviving Purkinje cells often show axonal swellings (‘torpedoes’). These are visible in the cerebellar granular layer as eosinophilic spheroids, but are better demonstrated by silver impregnation (Fig. 29.1e,f) or immunohistochemistry for neurofilament proteins. At the sites of loss of Purkinje cells, the persisting basket cell fibers form ‘empty baskets’ that can be demonstrated by silver impregnation (Fig. 29.1f,g). With loss of Purkinje cells there is proliferation of Bergmann astrocytes at the junction of the granular and molecular layers (Fig. 29.1 h). Bergmann astrocytes extend processes towards the pial surface in a regular radial pattern termed ‘isomorphic gliosis’ (Fig. 29.1i). Degeneration of Purkinje cells causes some loss of myelinated fibers from the cerebellar folia. In some conditions caused by triplet-repeat expansion within a gene, inclusion bodies can be detected in neuronal nuclei by use of appropriate immunohistochemical techniques, for example with antibody to ubiquitin or P62.

OLIVOPONTOCEREBELLAR ATROPHY (OPCA)

MACROSCOPIC AND MICROSCOPIC APPEARANCES

This pattern of pathology is seen in several types of degenerative ataxia. In addition to loss of neurons from the cerebellar cortex, as described in cerebellar cortical atrophy, there is macroscopic atrophy of the pons and medulla. Histologically, there is loss of neurons from the pontine and inferior olivary nuclei (Fig. 29.2). The term OPCA describes a pattern of pathology and does not imply any particular disease process.

AUTOSOMAL RECESSIVE CEREBELLAR ATAXIA

This pattern of inheritance accounts for the majority of patients with early onset disease. While Friedreich’s ataxia is the commonest condition in this group, many other uncommon conditions are identified. A full list is maintained on the website of the Neuromuscular Disease Center, at: http://neuromuscular.wustl.edu/ataxia/recatax.html.

FRIEDREICH’S ATAXIA (FA)

MACROSCOPIC AND MICROSCOPIC APPEARANCES

The brain is generally macroscopically unremarkable, although cardiomyopathy may have caused ischemic damage. The spinal cord and dorsal roots are typically atrophic. Histologic abnormalities involve several regions of the CNS:

The spinal cord shows degeneration and astrocytosis of the posterior columns, affecting the gracile more than the cuneate fasciculus, with distal degeneration of the pyramidal and spinocerebellar tracts (Fig. 29.3a,b). There is typically severe loss of neurons from Clarke’s column.

In the medulla, tract degeneration is accompanied by neuronal loss from the accessory cuneate and gracile nuclei, reflecting transneuronal degeneration. Cell loss and astrocytosis are seen in the vestibular and cochlear nuclei and in the superior olives. The inferior olives are generally normal.

In the cerebellum, the white matter may show astrocytic gliosis but the cerebellar cortex is usually normal. Hypoxic–ischemic damage caused by cardiomyopathy may produce secondary cerebellar cortical damage. Severe cell loss is seen in the dentate nuclei and is associated with marked atrophy of the superior cerebellar peduncle.

In the cerebral cortex there are generally no specific pathologic changes, but functional imaging studies have demonstrated cortical atrophy and reduced metabolism. Hypoxic–ischemic damage due to cardiomyopathy may produce secondary cortical damage.

There may be neuronal loss from the globus pallidus and the subthalamic nuclei.

Optic nerves and tracts usually show a slight loss of fibers.

Peripheral nerves show a loss of dorsal root ganglion cells (Fig. 29.3c) associated with severe depletion of large myelinated axons from the posterior roots (Fig. 29.3d) and sensory nerves.

FRIEDREICH’S ATAXIA

The prevalence is 1–2 per 100 000.

Onset is usually before the age of 15 years and is rare after 25 years, although late onset cases have been identified by genetic studies.

Patients typically present with ataxia of gait, and later, limb ataxia, dysarthria, loss of joint position and vibration sense in the lower limbs, generalized areflexia, pyramidal lower limb weakness, and extensor plantar responses. Ataxia is due to a combination of sensory neuropathy and the degeneration of cerebellar afferent and efferent fibers. Scoliosis and pes cavus are common.

Over 60% of patients develop cardiomyopathy, and approximately 10% diabetes mellitus.

Patients usually die by the end of their fourth decade.

Some clinical features previously regarded as essential for diagnosis may not be seen in some patients with Friedreich’s ataxia (early onset, areflexia, extensor plantar responses and reduced vibration sense)

GENETICS OF FRIEDREICH’S ATAXIA

The disease locus has been mapped to the centromeric region of chromosome 9q in FRDA, the gene that codes for the protein frataxin.

Frataxin is an 18 kDa mitochondrial protein of 210 amino acids, with some homology to proteins that regulate iron transport in mitochondria. It is located in the inner mitochondrial membrane. Reduced levels of frataxin probably cause accumulation of iron leading to oxidative damage to neurons.

The commonest mutation (95% of cases) is expansion of a GAA triplet repeat in the gene.

Normal number of repeats is between 6 and 34, whereas around 1000 repeats are present in most patients.

Late onset with relatively mild disease is seen in patients with fewer than 500 repeats.

Repeat numbers of around 1000 or more are associated with early disease onset, cardiomyopathy, reduced reflexes in the arms, and scoliosis.

In ~5% of cases, the disease is associated with point mutations in the gene.

CEREBELLAR ATAXIA WITH ISOLATED VITAMIN E DEFICIENCY

This is caused by mutations of the gene encoding α-tocopherol transfer protein, which is needed for the absorption of dietary vitamin E. The manifestations are indistinguishable from those of FA (i.e. ataxia, areflexia, sensory loss, and pyramidal weakness, sometimes accompanied by cardiomyopathy), but progression can be prevented by vitamin E supplements. In North Africa AVED (ataxia with vitamin E deficiency) is as common as FA.

MACROSCOPIC AND MICROSCOPIC APPEARANCES

Neuropathology is characterized by axonal spheroids with degeneration in the posterior columns. There is also loss of Purkinje cells. This is similar to that seen in vitamin E deficiency due to malabsorption resulting from pancreatic, liver, or intestinal disease (see Chapter 21).

MITOCHONDRIAL RECESSIVE ATAXIA SYNDROME

This is caused by mutation in a nuclear-encoded gene related to mitochondrial function, DNA polymerase-gamma gene (POLG). Mutation in POLG leads to mtDNA depletion in peripheral nerve and skeletal muscle. There are two main clinical syndromes, as follows:

Spinocerebellar ataxia with epilepsy (SCAE) develops in childhood and adolescence with cerebellar and sensory ataxia, dysarthria, ophthalmoplegia and myoclonus. Muscle biopsies may show cytochrome oxidase (COX)-negative fibers.

Sensory ataxia linked to peripheral neuropathy with dysarthria and ophthalmoplegia (SANDO) develops in adults. Skeletal muscle may shows myopathic changes with ragged-red, COX-negative fibers.

ATAXIA–TELANGIECTASIA (AT)

This is the commonest cause of progressive ataxia in infancy, with an incidence of at least 1/80 000 live births. This is one of the small group of disorders in which ataxia is linked to mutations in genes that also give rise to radiation sensitivity.

CLINICAL FEATURES OF ATAXIA TELANGIECTASIA

Children typically manifest with ataxia as soon as they begin to walk, and later develop dysarthria, chorea, and abnormal eye movements. The characteristic telangiectasia, which affects the sclera and skin, becomes prominent by the end of the first decade. There may be progeric changes of hair and skin.

Other features include:

Neurologic – areflexia, distal wasting, weakness, sensory loss and cognitive slowing.

Immunologic – impairment of cell-mediated and humoral immunity is common, and predisposes to recurrent infections, although some patients have relatively normal immune function and survive well into adult life.

Neoplasia – patients are predisposed to develop malignancies, especially T-cell leukemia and lymphomas, but also several types of carcinoma.

GENETICS AND PATHOGENESIS OF ATAXIA TELANGIECTASIA

AT is caused by mutations in a single large gene (AT-mutant; ATM) of about 170 kb. The 350 kDa protein product includes a carboxyl terminal domain with homology to the signal transduction mediator, phosphatidylinositol 3′-kinase.

Incidence: 1 in 40 000–300 000 births.

The ATM protein is involved in multiple aspects of cell cycle control and DNA damage surveillance (Fig. 29.4). It is normally a nuclear protein.

Cells from patients with AT are hypersensitive to radiation and exhibit chromosomal breakage, telomere shortening, and increased intrachromosomal recombination.

80–90% of patients with AT have mutations that are predicted to inactivate the ATM protein.

10–20% of AT families have a less severe clinical and cellular phenotype, associated with mutations that do not completely inactivate the protein.

MACROSCOPIC AND MICROSCOPIC APPEARANCES

The diverse multisystem abnormalities are summarized in Figure 29.5.

29.4 Pathogenetic mechanism of AT.
(a) In normal cells, cell cycle checkpoints at the G1, S, and G2 phases stop cell cycle progression after sublethal DNA damage, and induce DNA-repair systems. ATM gene product is involved in the surveillance of DNA damage. With cycle arrest there is induction of P53 protein and DNA repair can take place, leading to recovery. (b) In AT cells, this process is defective, and cells with damaged DNA can continue to divide. Induction of P53 protein associated with cell cycle arrest at the G1 checkpoint following DNA damage is impaired, leading to a disproportionate increase in apoptosis after low-level radiation damage. Initiation of inappropriate apoptosis in cells with non-lethal DNA damage is the probable reason for cell loss in the brain and lymphoid tissues.

29.5 Neuropathology of ataxia telangiectasia.

ATAXIA–TELANGIECTASIA-LIKE DISORDER

A small number of families have been found to have a clinically mild disease that is similar to AT but caused by mutations in a gene termed MRE11A, located at 11q21. The gene product is involved in DNA repair.

There is mild to moderate cell loss from the red nucleus, with associated gliosis (Fig. 29.6d). Mild neuronal loss and gliosis are evident in the caudate nucleus, putamen, thalamus, substantia nigra (Fig. 29.6e), and inferior olives. The superior cerebellar peduncles containing the efferent tracts from the dentate nuclei are atrophic and depleted of myelinated fibers. There may be degeneration of the spinocerebellar tracts and posterior spinal columns (Fig. 29.6f). In affected patients, the abnormal protein accumulates in neuronal nuclei both diffusely and as circumscribed ubiquitinated inclusions.

X-LINKED ATAXIAS

This pattern of inheritance accounts for a small proportion of patients with ataxia. The commonest condition in this group is fragile-X-associated tremor/ataxia syndrome. A small number of relatively uncommon conditions also fall into this group; a full list is maintained on the website of the Neuromuscular Disease Center, http://neuromuscular.wustl.edu/ataxia/recatax.html#xatax.

GENETICS OF DOMINANTLY INHERITED SPINOCEREBELLAR DEGENERATIONS

OMIM, Online Mendelian Inheritance in Man.

FRAGILE-X TREMOR/ATAXIA SYNDROME (FXTAS)

The fragile-X syndrome is caused by a CGG trinucleotide repeat expansion in the FMR1 gene. Expansions larger than 200 are associated with clinical disease presenting in childhood. Those who carry a lesser, fragile-X premutation expansion, typically 55–200 repeats in length, can develop a late-onset fragile-X-associated tremor/ataxia syndrome (FXTAS). While this mainly occurs in males (affecting 45% of male premutation carriers over 50 years of age), it can also present in female FMR1 premutation carriers (16% of women with premutations who are over 50 years of age). With increasing age, more individuals develop ataxia, the proportion reaching 75% in those over 80 years.

MACROSCOPIC AND MICROSCOPIC FEATURES

There may be generalized cortical atrophy with enlargement of the ventricles. Histologically, there is loss of Purkinje cells, with axonal torpedoes and Bergmann gliosis as described in cerebellar cortical atrophy. The cerebellar and cerebral white matter show degenerative

changes with patchy axon and myelin loss, in its most severe form leading to white matter vacuolation, described as spongiosis. There is usually involvement of subcortical arcuate fibers with sparing of periventricular white matter

Eosinophilic intranuclear inclusions can be seen diffusely in neurons in cortex, basal ganglia thalamus, midbrain and medulla. Inclusions have been reported in spinal autonomic neurons. Inclusions are not however seen in Purkinje cells. Inclusions are also widely seen in astrocytes including those in the cerebellum. Astrocytes are described as being dramatically enlarged. Inclusions may also be present in choroid plexus.

These intranuclear inclusions can be stained with anti-ubiquitin but do not label with antibodies against expanded polyglutamine tracts