Treatable Ataxias

Gluten ataxia (GA) has been defined as a sporadic otherwise idiopathic cerebellar ataxia associated with the presence of serological evidence of gluten sensitivity (usually antigliadin IgA or IgG with or without endomysium and transglutaminase antibodies) and has been shown in a one-year controlled trial to be responsive to a gluten-free diet¹⁴³.

Following an international consensus meeting GA is now accepted as one of the three commonest manifestations of autoimmunity to gluten ingestion which are: Coeliac disease (also known as gluten sensitive enteropathy), Dermatitis Herpetiformis and GA¹⁴⁴. The term Gluten-Related Disorders has been proposed to encompass all these entities.

Whilst antigliadin antibodies can be used in aiding the diagnosis of GA, these are found in up to 12% of the healthy population¹⁴⁵. Therefore it is important not to rely solely on testing for antigliadin antibodies. More specific antibodies have been identified and in particular antibodies against TG6 appear to be very promising in the diagnosis of GA^146,147. This test is not yet widely available. However, it should be considered if gluten ataxia is suspected. Neurologists are often faced with weighing up the options of whether or not to recommend a gluten-free diet in the context of a patient with idiopathic sporadic ataxia (when all other causes excluded) and positive antigliadin antibodies in the absence of enteropathy.

For those patients with gluten ataxia who also have an enteropathy, the recommendation is that they should go on a gluten-free diet without delay. For those patients with ataxia and no enteropathy, but with serological evidence of gluten sensitivity, it is advisable to recommend a gluten-free diet with dietetic advice and close monitoring.

The trial mentioned above did demonstrate that even those patients without enteropathy benefited from a gluten-free diet. Patients should however be made to understand that such benefit can only be seen with strict adherence to the diet, with evidence of elimination of the antibodies (that need to be tested on a six-monthly basis). Any improvement in ataxia or stabilisation of symptoms usually manifests within a year on a strict diet.

In some patients where there is evidence of cerebellar atrophy the expected benefit will be in the form of stabilisation rather than improvement. Monitoring can take the form of the ‘Scale for the Assessment and Rating of Ataxia’ ¹⁴⁸.

Some patients have shown benefit from the use of intravenous immunoglobulin therapy, however this has only been shown in case reports or small trials¹⁴⁹.

Ataxia with Vitamin E deficiency (AVED) is a rare recessively inherited form of ataxia caused by mutations in the TTPA gene that often results in similar symptoms to Friedreich’s ataxia. A genetic test can confirm the diagnosis. In these patients, serum vitamin E levels are significantly reduced. Vitamin E deficiency can also be caused by malabsorption of fat-soluble vitamins, as can be seen in a syndrome called abetalipoproteinemia, which also has ataxia as one of its symptoms.

Diagnosis of Vitamin E deficiency needs to be made in the context of serum lipid levels, also known as lipid adjusted vitamin E, as estimation of free levels of vitamin E is not reliable and can be misleading (normal range for lipid adjusted vitamin E is 3.9-5.9 units but may vary between labs). Patients diagnosed with Ataxia due to Vitamin E deficiency should be given vitamin E supplements. The daily dose of vitamin E required is much higher than what is used for other deficiency states (doses range from 800mg/day to 1500mg/day or 40mg/kg per day in children)¹⁵⁰. Treatment of presymptomatic children can prevent the development of ataxia. Studies have shown treatment leads to cessation of progression of neurological symptoms and mild improvement in certain patients, especially in the early stages of the disease¹⁵⁰. Abetalipoproteinemia can also be treated with vitamin E supplements¹⁵¹.

Diagnosis of this type of ataxia is very important so that early treatment with supplements can commence.

Patients who are deficient in Vitamin B12 can sometimes have similar symptoms to Freidreich’s ataxia, hence it is important to test Vitamin B12 levels. This condition can be treated with Vitamin B12 supplements¹⁵². If a patient is diagnosed with ataxia with Vitamin B12 deficiency they should be referred to a haemotologist, who will administer treatment. Depending on severity of symptoms treatment can be parenteral or oral with cyanocobalamin or hydroxocobalamin.

Ataxia with primary Coenzyme Q10 (CoQ10) deficiency is an autosomal recessive condition associated with mutations in the ADCK3 gene¹⁵³(also known as the CABC1 gene¹⁵⁴). The level of CoQ10 in skeletal muscle in these patients is usually below the normal range (variable between laboratories). Classification as ARCA2 (Autosomal Recessive Cerebellar Ataxia-2) has been suggested¹⁵³. Originally characterised by childhood onset ataxia and exercise intolerance¹⁵⁵, recently patients with adult onset ataxia have also been identified¹⁵⁶. Severity is variable; some individuals develop seizures and mild mental impairment.

Patients with this form of ataxia may improve with CoQ10 supplementation, hence the importance of early diagnosis^155–157. The exact dose and form of supplementation is not clear to date. However, a high dose of CoQ10 supplementation (500-1000 mg/day) is suggested in these patients. Although not all patients respond, given that AVED is a potentially treatable condition it is advisable to treat with CoQ10 supplementation.

Some patients with AOA2 (APTX gene mutations) and mutations in the ANO10 gene have also responded to CoQ10 therapy (200-500 mg/day)^158,159. In these forms of ataxia the CoQ10 deficiency is secondary, and not due to a defect in CoQ10 biosynthesis.

Testing of CoQ10 deficiency can be performed on skeletal muscle samples or on blood mononuclear cells²³.

Cerebrotendinous xanthomatosis is a sterol storage disorder characterized by the accumulation of cholestanol and cholesterol in tendons, the central nervous system and the lenses. It is an autosomal recessive condition that can affect children and adults. Chronic diarrhoea from infancy may be the earliest clinical manifestation. In approximately 75% of affected individuals, cataracts are the first finding, often appearing in the first decade of life¹⁶⁰. Diagnosis is by clinical and biochemical testing; a genetic test is also available.

Treatment with chenodeoxycholic acid may result in stabilisation or partial reversal of the neurological symptoms in some patients¹⁶⁰. Early diagnosis and initiation of therapy is important because some patients with established cholestanol deposits in the brain continue to deteriorate despite treatments^160,161.

NPC is a rare multi-system disease caused by accumulation of cholesterol and glycosphingolipids in the brain and other organs and ataxia may be a presenting symptom. A mean delay from onset to diagnosis of 6 years reflects its varied presentation. However, with the emergence of treatment that may slow the neurodegenerative aspects, international guidelines were updated in 2012 summarising presentation, diagnosis and management¹⁶².

Presentation

Severe cases present in infancy with cholestatic jaundice or acute respiratory failure. However, a more ‘typical’ presentation is in the second or third decade with one or more of:

• visceral signs that are readily missed at the bedside but frequently present on imaging (hepatomegaly in >50% and/or splenomegaly >90%)
• psychiatric disturbance (depression, acute psychosis or cognitive changes)
• a neurological syndrome that may include ataxia (limb and gait ataxia, dysarthria, dysphagia), an eye movement disorder (classically a vertical supranuclear gaze palsy), dystonia, myoclonus, epilepsy, cataplexy, or cognitive decline.

Cases have been reported with onset as late as mid sixth decade or the neurological features are missed or erroneously ascribed to side effects of psychotropic medication. The NP-C Suspicion index has been developed as a tool to help clinicians diagnose this treatable condition¹⁶²

Investigation

Diagnosis has been is hampered by the lack of a simple, reliable test. Chitotriosidase (frequently available as part of white cell enzymes panel) may be mildly elevated. MR brain scans are normal or non-specifically abnormal with cortical or cerebellar atrophy mirroring the clinical picture. Tissue diagnosis of bone marrow biopsy (foam cells) is unreliable, as is the gold standard of skin biopsy, culture and filipin staining–which can be normal in variant cases which are more likely to present later in adulthood.

Genetic testing of the two causative genes (NPC1 in 95% of cases and NPC2 in 5% of cases) provides a more definitive diagnosis. In addition, measurement of plasma oxysterols shows promise as an inexpensive screening tool¹⁶³. This diagnostic test is now available for the diagnosis of NPC at the Willink Biochemical Genetics Laboratory (Central Manchester University Hospitals NHS FT) and also the laboratory at Great Ormond Street Hospital.

Management

Symptomatic treatments for the psychiatric manifestations (antidepressants and/or antipsychotic medication) and the neurodegenerative aspects (anticonvulsants, gastrostomy feeding) have historically been the mainstay. However, it is now known that administration of Miglustat has been shown in studies to reduce the accumulation of glycosphingolipids and may slow the neuropsychological decline as well as stabilizing the progression of other neurological manifestations^164–168. It is the approved disease–modifying treatment for the treatment of paediatric and adult NPC and is available in the UK via Specialist Centres (see below for a list).

Details of Specialist NPC Centres:

Paediatric Niemann-Pick Disease patients:

• Great Ormond Street Hospital for Children NHS Foundation Trust
• Central Manchester University Hospitals NHS Foundation Trust
• Birmingham Children’s Hospital NHS Foundation Trust

Adult Niemann-Pick Disease patients:

• Salford Royal NHS Foundation Trust
• University Hospitals Birmingham NHS Foundation Trust
• University College London Hospitals NHS Foundation Trust
• Royal Free Hampstead NHS Trust

At the time of writing arrangements are in place for patients from Scotland, Wales and Northern Ireland to be seen within the designated Centres in England for diagnosis and clinical management. Decisions on funding treatment/access remain with the patient’s local health authority.