Inherited Metabolic Disorders Presenting with Ataxia

Ataxia is a common clinical feature in inherited metabolic disorders. There are more than 150 inherited metabolic disorders in patients presenting with ataxia in addition to global developmental delay, encephalopathy episodes, a history of developmental regression, coarse facial features, seizures, and other types of movement disorders. Seizures and a history of developmental regression especially are important clinical denominators to consider an underlying inherited metabolic disorder in a patient with ataxia. Some of the inherited metabolic disorders have disease specific treatments to improve outcomes or prevent early death. Early diagnosis and treatment affect positive neurodevelopmental outcomes, so it is important to think of inherited metabolic disorders in the differential diagnosis of ataxia.


Introduction
Coordination and balance are controlled by a complex network system including the basal ganglia, cerebellum, cerebral cortex, peripheral motor, and sensory pathways. The cerebellum contributes to coordination, quality of movement, and cognition. There are a large number of inherited metabolic disorders affecting the cerebellum and resulting in cerebellar atrophy or hypoplasia [1,2].
Ataxia is described as abnormal coordination secondary to cerebellar dysfunction, vestibular dysfunction, or sensorial dysfunction. Ataxia can present as gait ataxia, truncal ataxia, tremor, or nystagmus depending on the involved parts of the nervous system [3,4]. All types of ataxia can present individually or in combination in a single patient. Ataxia can be an important part of the clinical picture in inherited metabolic disorders which can guide physicians to targeted investigations to identify underlying causes. This is particularly important for diagnosing treatable inherited metabolic disorders to improve neurodevelopmental outcomes.
Ataxia is usually part of a complex phenotype in inherited metabolic disorders. There are several important features and signs to point towards inherited metabolic disorders ( Figure 1). In medical history, the presence of recurrent somnolence and coma episodes during intercurrent illnesses, a history of protein aversion or failure to thrive, a history of progressive loss of skills, hearing loss, hair abnormalities, behavioral problems, and seizures in combination with ataxia and global  Some of the inherited metabolic disorders can present with episodic or intermittent ataxia during intercurrent illness, stress situations, or prolonged fasting. This is due to an increased energy demand and decreased energy production due to the defects in energy metabolism pathways and in the production or transport of fuels such as glucose and ketone bodies, or the increased production of toxic metabolites such as amino acids or organic acids secondary to catabolism. Episodic or intermittent ataxia can be observed in maple syrup urine disease, pyruvate dehydrogenase complex (PDHC) deficiency, and GLUT1 deficiency. In progressive neurodegenerative disorders, e.g., lysosomal storage disorders, ataxia is usually progressive. In energy metabolism disorders, ataxia is usually static with acute episodes of deterioration during intercurrent illnesses. It is important to remember these disorders to initiate diagnostic investigations and start appropriate treatment.
Recently, we reported the genetic landscape of pediatric movement disorders. Ataxia was the most common movement disorder in 53% of the patients who underwent genetic investigation in our clinic [6]. Interestingly, 74% of patients with ataxia had 16 different underlying genetic diseases. There were 8 different inherited metabolic disorders including GLUT1 deficiency, SURF1 Leigh's disease, PDHC deficiency, DNAJC19 disease, ND3 mitochondrial encephalopathy, NCL type 2, riboflavin transporter deficiency, and 3-hydroxy-3-methylglutaryl CoA synthase 2 deficiency [6]. Seizure and a history of developmental regression are especially important clinical denominators when considering the underlying inherited metabolic disorders in patients with ataxia.
Cerebellar atrophy in brain magnetic resonance imaging (MRI) can be found in mitochondrial disorders (e.g., mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), neuropathy, ataxia, and retinitis pigmentosa (NARP), Kearns-Sayre syndrome, leukoencephalopathy with brain stem, spinal cord involvement, and lactate elevation, PDHC deficiency, primary coenzyme Q10 deficiency, POLG disease), lysosomal storage disorders (metachromatic leukodystrophy (MLD), GM2 gangliosidosis, Niemann-Pick type C (NPC), Salla disease, NCL, fatty acid hydroxylaseassociated neurodegeneration), classical galactosemia, L-2-hydroxyglutaric aciduria, Menkes disease, and mevalonate kinase deficiency [1,2]. Table 1 summarizes the vast majority of inherited metabolic disorders presenting with ataxia, including category of inherited metabolic disorders, genes, and clinical features. Table 2 lists metabolic investigations. Disease-specific treatments to improve outcomes in inherited metabolic disorders are summarized in Table 3 [5,. We provide a list of disorders based on the specific clinical features in Figure 1 [36]. In this review article, we list some of the treatable inherited metabolic disorders in details below.

Maple Syrup Urine Disease (MSUD)
Maple syrup urine disease (MSUD) is an autosomal recessive disorder of branched chain amino acid (leucine, valine, isoleucine) catabolism due to branched-chain alpha-ketoacid dehydrogenase complex (BCKD) deficiency encoded by BCKDHA, BCKDHB, and DBT genes [7,8]. The BCKD complex deficiency results in the accumulation of leucine, valine, isoleucine, and alloisoleucine [7,9]. Its estimated incidence is 1 in 185,000 live births, with a higher prevalence of up to 1 in 113 in Ashkenazi Jewish populations due to a founder pathogenic variant in BCKDHB (c.548G > C) [7].
Phenotypes of MSUD consist of classical, intermediate, intermittent, and thiamine responsive [7,8]. The classical MSUD, or severe neonatal onset form, presents in the first week of life with feeding intolerance, encephalopathy, and seizures. Characteristic maple syrup odor can be present in cerumen as early as 12 hours [7][8][9]. If left untreated, the severe neonatal onset form may progress to coma or death secondary to brain edema [8]. Intermediate and intermittent forms typically manifest during any age ranging from infantile to adulthood. Clinical features of the intermediate form include global developmental delay, failure to thrive, maple syrup urine smell, and intermittent episodes of encephalopathy during intercurrent illnesses [7,8]. Usually, patients with the intermittent form may have normal early development and growth and can be missed until a catabolic state or intercurrent febrile illness when ataxia may manifest as an initial presentation [7,8]. The clinical presentation of the thiamine responsive form is similar to the intermediate form and is responsive to thiamine supplementation.
In the neonatal period, the acute elevation of leucine levels results in fencing and bicycling movements, irritability, and opisthotonos. In older children, the acute elevation of leucine levels results in acute neurological deterioration characterized by an altered level of consciousness, acute dystonia, and ataxia which may progress to coma. Hyperactivity, sleep disturbances, and hallucinations are also reported.
Patients with classical MSUD can be identified by positive newborn screening for MSUD or with the above symptoms. Plasma amino acid analysis reveals elevated leucine, alloisoleucine, valine, and isoleucine. Elevated ketones may cause metabolic acidosis. Ammonia is usually normal in MSUD patients but may be mild to moderately elevated during acute metabolic decompensations in some patients [9]. Intermediate and intermittent forms are often missed by newborn screening due to higher BCKD activity resulting in initial normal leucine plus isoleucine levels [7,8]. Plasma amino acid analysis can be normal or mildly elevated in intermittent forms of MSUD outside of metabolic decompensations. In patients with episodes of ataxia during intercurrent illness, plasma amino acid analysis is highly recommended; if plasma amino acid analysis is not collected during an acute metabolic decompensation, the intermittent form of MSUD can be missed.
Treatment consists of a dietary restriction of leucine, supplementation of valine and isoleucine, and branched chain amino acid free medical formula. During intercurrent illness, caloric intake should be increased to prevent catabolism and leucine elevation, which could result in acute encephalopathy and brain edema [7,8]. If medical treatment is not successful in decreasing leucine levels, hemodialysis is undertaken to remove leucine and prevent coma and death due to leucine toxicity [9]. If patients require strict leucine restriction and several hospital admissions during intercurrent illnesses, non-related orthotopic liver transplantation is the treatment of choice [9].

Galactose-1-phosphate Uridylyltransferase Deficiency
Galactose-1-phosphate uridylyltransferase (GALT) deficiency is an autosomal recessive disorder of the galactose metabolism. Galactosemia is due to biallelic pathogenic variants in GALT [10]. Its prevalence is 1 in 48,000 as per the National Newborn Screening and Genetics Resources Center. It is more common in Ireland with a prevalence of 1 in 16,476 [11,12]. GALT deficiency results in the accumulation of galactose, galactose-1-phosphate, and galactitol [10][11][12].
Classical galactosemia patients present in the neonatal period with feeding problems, hepatic failure, and coagulopathy that can acutely progress to multi organ failure and potentially death if untreated [10][11][12]. Despite adequate treatment with galactose restricted diet, patients can suffer from developmental delay, speech delay, and motor dysfunction presenting with ataxia and tremor. Females are at risk of gonadal dysfunction and premature ovarian insufficiency [11,12].
The long-term neurodevelopmental outcome is characterized by speech problems, learning difficulties, and cognitive dysfunction even in treated patients. A small number of patients present with tremor, either intentional or postural, cerebellar ataxia, and dystonia.
The National Newborn Screening Programs included galactosemia in their list of disorders to identify and treat newborns early. Diagnosis is confirmed by the measurement of erythrocyte galactose-1-phosphate concentration or reduced GALT enzyme activity [11]. Treatment consists of dietary lactose and galactose restriction [10].

Glucose Transporter 1 (GLUT1) Deficiency
Glucose is transported from the bloodstream to the central nervous system by glucose transporter 1 (GLUT1), encoded by SLC2A1. A genetic defect in this transporter protein results in impaired glucose supply to the brain, affecting brain development and function, called GLUT1 deficiency. Since its first description, there have been about 400 patients reported in the literature [13]. It is an autosomal dominant disorder caused by heterozygous pathogenic or likely pathogenic variants in SLC2A1.
The phenotype ranges from early onset severe global developmental delay, epileptic encephalopathy, acquired microcephaly, ataxia, dystonia, and spasticity to paroxysmal movement disorder including intermittent ataxia, choreoathetosis, dystonia, and alternating hemiplegia with or without cognitive dysfunction or intellectual disability. In a study, 57 patients with GLUT1 deficiency were reported with their distribution of movement disorders. Ataxia and ataxia plus spastic gait were the most common movement disorder in 70% of the patients. Ataxia improved after feeding in some of the patients [14].
The characteristic biomarker is low cerebrospinal fluid (CSF) glucose or low CSF to blood glucose ratio in the presence of normal blood glucose. Blood glucose should be collected within 30 min prior to lumbar puncture. If blood glucose is not collected, the CSF glucose level is also helpful to guide the diagnosis of GLUT1 deficiency. The CSF-to-blood glucose ratio ranges between 0.19 and 059 and the CSF glucose ranges between 0.9 and 2.88 mmol/L in patients with GLUT1 deficiency [13]. The diagnosis is confirmed by either a genetic test using targeted next generation sequencing for epilepsy, movement disorders, intellectual disability, or whole exome sequencing. In patients with low CSF glucose levels, direct Sanger sequencing of SLC2A1 can be applied to confirm the diagnosis [13]. In about 90% of patients, diagnosis is confirmed by sequence analysis and in about 10% of the patients, a deletion/duplication test is important to apply to identify small deletion and duplications.
The ketogenic diet has been the gold standard for the treatment of GLUT1 deficiency. The response to treatment varies depending on the age of diagnosis and application of the ketogenic diet. About 65% of patients become seizure free in one week to one month of the ketogenic diet therapy. It is recommended that beta-hydroxybutyrate levels are kept at 4-5 mM. The response to the ketogenic diet is variable.

Creatine Deficiency Disorders
Arginine, glycine amino acid, L-arginine:glycine amidinotransferase (AGAT), and guanidinoacetate N-methyltransferase (GAMT) are involved in creatine synthesis in the kidney and liver. After synthesis, creatine is taken up by high energy demanding organs, such as the brain, muscles, and the retina by an active sodium chloride dependent creatine transporter (CRTR). There are three disorders involving synthesis and transport of creatine, including AGAT, GAMT, and CRTR deficiencies. The first two enzyme deficiencies are inherited autosomal recessively while CRTR deficiency is an X-linked disorder. They are ultra-rare disorders with less than 130 patients with GAMT deficiency, less than 20 patients with AGAT deficiency, and less than 200 patients with CRTR deficiency reported so far [15].
Global developmental delay and cognitive dysfunction are the most common clinical features and present in all untreated patients in the three creatine deficiency disorders. Epilepsy, movement disorders, and behavioral problems are observed in GAMT and CRTR deficiencies. The phenotype ranges from asymptomatic to severe phenotypes in females in CRTR deficiency. GAMT deficiency leads to complex movement disorders in combination with ataxia and tremor; choreoathetosis and dystonia; dystonia, chorea, and ataxia; myoclonus and bradykinesia; or ballismus and dystonia [16]. In a study, 50% of the patients who were older than 6 years of age at the time of the diagnosis of GAMT deficiency presented with ataxia [17]. In 101 male patients with CRTR deficiency, a wide based gait, ataxia, dysarthria, and coordination problems were reported in 29% of them [18].
The biochemical hallmarks are cerebral creatine deficiency in brain magnetic resonance spectroscopy ( 1 H-MRS) in GAMT and AGAT deficiencies as well as in males with CRTR deficiency. Urine, plasma, and cerebrospinal fluid (CSF) guanidinoacetate is elevated in GAMT deficiency, low in AGAT deficiency, and normal in CRTR deficiency. The urine creatine is elevated in males with CRTR deficiency. Females can have a normal or mildly elevated urine creatine. In the presence of abnormal biochemical features, Sanger sequencing of GAMT, GATM or SLC6A8 confirms the diagnosis of these disorders [15].
Creatine supplementation is applied in all creatine deficiency disorders. Ornithine supplementation and protein-or arginine-restricted diet are applied in GAMT deficiency. Arginine and glycine supplementation are applied in CRTR deficiency [15]. Epilepsy improves in about two-thirds of the patients with GAMT deficiency and movement disorder improves in about 50% of the patients with GAMT deficiency.

Primary Coenzyme Q10 Deficiency
Coenzyme Q10 is an essential cofactor involved in various cellular pathways including the electron transport chain, the beta oxidation of fatty acids, and pyrimidine biosynthesis [19]. There are more than 10 genetic defects involved in the coenzyme Q10 biosynthesis causing primary coenzyme Q10 deficiency (Table 1) [19,20]. The genes associated with primary coenzyme Q10 deficiency are listed in Table 1. Inherited primary coenzyme Q10 deficiency disorders are autosomal recessive disorders [20].
The clinical features of primary coenzyme Q10 deficiency are complex and involve multiple organs or systems including global developmental delay, cognitive dysfunction, seizures, ataxia, movement disorder, spasticity, cardiomyopathy, hearing loss, peripheral neuropathy, and retinopathy [19,20].
A definitive biochemical diagnosis is confirmed by deficient coenzyme Q10 amounts in muscle biopsy specimen and skin fibroblasts [19,20]. The biochemical diagnosis is confirmed by either targeted next generation sequencing panel for coenzyme Q10 deficiency or by whole exome sequencing.
Treatment consists of oral coenzyme Q10 supplementation, which is well tolerated. The response to the treatment is variable and treatment outcome data is sparse [19,20].

Biotinidase Deficiency
Biotinidase deficiency is an autosomal recessive disorder due to the biallelic pathogenic variants in BTD, encoding biotinidase [21]. Biotinidase is responsible for the recycling of biotin from biocytin to contribute to the free biotin pool. Biotin is an important cofactor for the conversion of apocarboxylases to holocarboxylases, including pyruvate carboxylase, 3-methylcrotonyl-CoA carboxylase, propionyl CoA carboxylase, and acetyl-CoA carboxylase [21,22]. Biotinidase deficiency is sometimes referred to as late onset multiple carboxylase deficiency, as biotin deficiency impacts numerous enzymatic processes [22]. Its estimated prevalence is 1 in 60,000 worldwide, including 1 in 137,000 for profound and 1 in 110,000 for partial biotinidase deficiency [22,23]. In some expanded newborn screening programs, biotinidase deficiency is included to identify newborns in the asymptomatic stage.
Profound biotinidase deficiency can present with seizures, alopecia, hypotonia, and skin rash in the first few months of life. If left untreated, patients present with global developmental delay, ataxia, optic atrophy, ophthalmological problems, and hearing loss [21][22][23]. Older patients with later onset tend to display ataxia and movement disorders as initial clinical presentations [23].
Untreated biotinidase deficiency has numerous biochemical abnormalities including metabolic acidosis, hyperammonemia, or lactic acidosis which may present as an acute metabolic decompensation during intercurrent illness [22]. An abnormal acylcarnitine profile and urine organic acid analysis are suggestive and biochemical diagnosis is confirmed by deficient biotinidase activity in serum. If the biotinidase activity is less than 10% normal, it is called profound deficiency. If the biotinidase activity is 10-30% normal, it is called partial deficiency [23].

Riboflavin Transporter Deficiency
Riboflavin is a precursor of flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), which are crucial cofactors for the electron transport chain and beta oxidation of fatty acids in the mitochondria for energy production. To maintain riboflavin metabolism in the human body, riboflavin is transported across membranes using riboflavin transporters including RFVT1, encoded by SLC52A1, RFVT2, encoded by SLC52A2 and RFVT3, encoded by SLC52A3. Biallelic pathogenic variants in SLC52A2 and SLC52A3 are reported in human disease after 2010. Both genetic defects are associated with previously known Brown-Vialetto-Van Laere (BVVL) and Fazio-Londe (FL) syndromes [24]. Disease onset ranges from early infantile onset to early adulthood onset. Usually, a history of developmental regression is the initial symptom. Symptoms range from motor dysfunction, muscle weakness, hypotonia, ataxia, failure to thrive, or hearing loss to peripheral neuropathy. Bulbar symptoms, respiratory failure, and optic atrophy are also common features. These are progressive disorders, if untreated.
Diagnosis is suspected by acylcarnitine profile and urine organic acid abnormalities resembling multiple acyl-CoA dehydrogenase deficiency or ethylmalonic aciduria. Complex II deficiency in muscle biopsy has been reported in two patients with riboflavin transporter deficiency [25].
Diagnosis is confirmed either by the direct Sanger sequencing of SLC52A2 and SLC52A3 genes or the application of targeted next generation sequencing panels for nuclear mitochondrial disorders or whole exome sequencing.
High dose oral riboflavin supplementation is the treatment. The timing of treatment onset is essential for favorable treatment outcomes [24,25].

Organelle Related Disorders: Lysosomal Storage Disorders
Neuronal Ceroid Lipofuscinosis (NCL) Neuronal ceroid lipofuscinoses (NCL) are the most common lysosomal storage disorders with an estimated prevalence of 1.5 to 9 per a million people [26]. There are more than 10 subtypes. The most common subtypes are type 2, CLN2, and type 3, CLN3 diseases. Disease onset ranges from infantile to adulthood even within the same subtype.
Clinical features are characterized by a history of developmental regression in motor and cognitive functions, seizures, visual problems, and early death [27]. Progressive ataxia is a common feature in NCL secondary to progressive cerebellar atrophy [6]. The first symptom is usually a seizure which is followed by developmental regression. Motor dysfunction is characterized by myoclonus in infants and ataxia and spasticity in older children.
Three of the NCL genes encode an enzyme, cathepsin D, encoded by CTSD; palmitoyl-protein thioesterase, encoded by PPT1 or CLN1, and tripeptidylpeptidase 1, encoded by TPP1 or CLN2 [28]. Granular osmiophilic, curvilinear, and fingerprint lipopigments identified by the electron microscopic examination of lymphocytes, skin cells, or cells from conjunctival biopsy are the suggestive neuropathological features of NCL. The diagnosis is confirmed by targeted Sanger sequencing, the application of an NCL panel, or whole exome sequencing. Many NCL genes are also included in targeted next generation sequencing panel for epilepsy [29].
Treatment is symptomatic for the majority of NCL. Recently, intracerebroventricular cerliponase alfa infusions for the treatment of CLN2 (TPP1) disease was approved for clinical use [27,30]. Trials for CLN3 and CLN6 are underway in clinical Phase I/II human studies.

Organelle Related Disorders: Peroxisomal Disorders
2.6.1. X-linked adrenoleukodystrophy (X-ALD) X-linked adrenoleukodystrophy (X-ALD) is due to hemizygous pathogenic variants in ABCD1, which encodes ATP-binding cassette domain 1 (ABCD1). This protein is a peroxisome transporter protein. Due to the pathogenic variants and ABCD1 dysfunction, very long chain fatty acids accumulate, especially in the adrenal glands and the brain. Its estimated prevalence is 1 in 20,000 males [31].
The age of symptom onset is variable and ranges from childhood to adulthood. The most severe form is the childhood onset cerebral form. After normal cognitive and motor function, males present with behavioral problems, followed by progressive motor and cognitive dysfunction and progressive ataxia between the ages of 4 and 8 years, leading to complete motor and cognitive dysfunction within a few years. The cerebral form can also be seen in adolescents and adults with a slower disease progression [31]. Adrenal insufficiency is a common feature requiring hormone replacement therapy.
Adrenomyeloneuropathy is the most common phenotype, with spinal cord disease leading to chronic progressive spasticity, neuropathy, and incontinence [31,32].
The diagnosis is suspected by characteristic brain MRI features including symmetrical increased signal intensity in parieto-occipital region in T2 weighted images. Active demyelination areas are enhanced with contrast. The biochemical hallmark is elevated plasma very long chain fatty acids. The diagnosis is confirmed by direct sequencing and deletion/duplication analysis of ABCD1 [31,32].
The treatment is hematopoietic stem cell transplantation (HSCT) in males, with disease progression stopping after HSCT. The decision for HSCT depends on disease morbidity. In males with extensive white matter changes, motor, and cognitive dysfunction, HSCT is not recommended [31,32].
The age of onset ranges from 7 months to older than 50 years. Retinitis pigmentosa and anosmia are early clinical features. About 10-15 years later, neuropathy, ataxia, muscle weakness, sensory loss, deafness, and ichthyosis are the part of the clinical features. Initially, patients present with an unsteady gait which progresses to ataxia as a result of cerebellar dysfunction. Additionally, motor and sensory polyneuropathy, skeletal abnormalities, and cardiac arrhythmias have been reported [35].
Elevated plasma phytanic acid and pipecolic acid suggest the diagnosis of Refsum disease. The diagnosis is confirmed by direct Sanger sequencing of PHYH [35].
The treatment consists of phytanic acid restricted diet. This diet can improve polyneuropathy, ataxia and ichthyosis and arrhythmias due to decrease in plasma phytanic acid levels. In acute onset arrhythmias and severe weakness, plasmapheresis or lipopheresis can be used to improve symptoms. Weight loss or decreased caloric intake mobilizes stored lipids and causes the acute deterioration of symptoms, which should be avoided by a high caloric intake diet [35].

Conclusions
Inherited metabolic disorders are individually rare. Some inherited metabolic disorders have disease-specific treatments to improve neurodevelopmental outcomes and to prevent early death. It is important to think of inherited metabolic disorders in the differential diagnosis of ataxia.
A medical history of somnolence and coma during intercurrent illness, the progressive loss of skills, hearing loss, behavioral problems, seizures, and global developmental delay are important to suggest inherited metabolic disorder. A history of developmental regression is an important symptom to suggest lysosomal storage disorders. Detailed three-generation family history can help identifying X-linked, autosomal dominant, or mitochondrial disorders. A family history of global developmental delay, cognitive dysfunction, psychiatric disorders, recurrent miscarriage, sudden infant death syndrome, and congenital malformations can suggest inherited metabolic disorders. A detailed review of neuroimaging can identify specific neuroimaging features to suggest specific inherited metabolic disease. For example, progressive ataxia and cerebellar atrophy in brain MRI is suggestive of neuronal ceroid lipofuscinosis. If there is any specific clinical, or neuroimaging feature to suggest a particular inherited metabolic disease, appropriate metabolic investigations can be performed to support the diagnosis. The diagnosis is confirmed by targeted direct Sanger sequencing. If there is no specific clinical, biochemical, or neuroimaging feature, non-targeted genetic investigations including targeted next generation sequencing panel or whole exome or mitochondrial genome sequencing are applied to reach a diagnosis.