Neurological presentations of treatable neurometabolic disorders

Administrator: Suvasini Sharma

Treatable neurometabolic neuromuscular disorders
Ingrid Tein

These disorders can be divided into primary disorders of mitochondrial vitamin-cofactor metabolism such as Brown-Vialetto-Van Laere syndrome (SLC52A2, SLC52A3) and Fazio-Londe disease (SLC52A3), which present with cranial nerve palsies and sensorineural hearing loss (in the former), and respond to high dose riboflavin. Disorders with an indirect response to riboflavin therapy include ACAD9 deficiency which presents with myopathy and hypertrophic cardiomyopathy and multiple acyl-CoA dehydrogenase deficiency (ETFA, ETFB, ETFDH, etc.) which present with early childhood onset multisystemic disease or late onset muscle weakness.  ETFDH deficiency, which presents with proximal myopathy and exercise intolerance, responds to CoQ10 + riboflavin. Disorders of Coenzyme Q10 biosynthesis (PDSS1, PDSS2, C0Q2, C0Q4, C0Q6, C0Q7, ADCK3, ADCK4, C0Q9) have variable phenotypes ranging from fatal neonatal presentations to adult-onset myopathy/recurrent myoglobinuria which respond variably to high dose CoQ10. The high-affinity carnitine transporter defect (SLC22A5) presents with infantile onset myopathy and cardiomyopathy and responds to high dose oral L-carnitine which reverses the phenotype. In this talk, new phenotypes of treatable metabolic myopathies and neuropathies and recent advances in diagnosis and treatments will be discussed. The earlier the diagnosis and specific vitamin/cofactor intervention, the better the outcome with a reduction in critical morbidity and mortality.
 

Treatable neurometabolic epilepsies
Suvasini Sharma

Seizures and epilepsy are frequently encountered in neurometabolic disorders. Several of these are amenable to specific treatments, e.g. Vitamin B6 dependent epilepsy, biotinidase deficiency, glucose transporter defect, MTFHR deficiency, and to a certain extent epilepsy associated with mitochondrial disorders. Early diagnosis and treatment of these disorders is important to provide specific treatments, avoid potentially harmful anti-seizure medications such as sodium valproate and prevent the development metabolic crises and improvement of neuro-developmental outcomes. Ketogenic diet therapies are the treatment of choice for glucose transporter defect and are also effective in some mitochondrial epilepsies. Vitamin B6 dependent epilepsies are a group of treatable diseases (ALDH7A1 deficiency, PNPO deficiency, PLP binding protein deficiency, hyperprolinaemia type II and hypophosphatasia and glycosylphosphatidylinositol anchor synthesis defects) responding to pyridoxine or pyridoxal-5I-phosphate. Apart from vitamin B6 supplementation, alternative treatment strategies for ALDH7A1 deficiency include lysine-restricted diet, arginine supplementation, oligonucleotide antisense therapy, upstream inhibition of aminoadipic semialdehyde synthase. In this talk, new phenotypes of treatable metabolic epilepsies and recent advances in diagnosis and treatments of neurometabolic disorders presenting with epilepsy will be discussed.
 

Treatable neurometabolic causes of intellectual disability and autism spectrum disorders
Arushi Saini

With advancements in diagnostics, neurometabolic disorders are being increasingly recognized as the underlying cause for global developmental delay, intellectual disability, autism and other neurodevelopmental phenotypes. These entities were previously considered untreatable, but with therapeutic advances, several of these disorders are now considered ‘treatable.’ Currently, nearly 90 treatable IDs are recognized and several of these are neurometabolic in origin. With this session, we aim to increase the awareness and avoid the diagnostic and treatment delays often suffered by rare diseases patients. In this session, we attempt to discuss the IMDs which present with neurodevelopmental phenotype, yet are amenable to interventions targeting pathophysiology (e.g., nutraceutical, pharmacological, surgical, etc.) if initiated in a timely fashion. Although there are gaps in patient care between developed and developing countries, yet with increasing collaborations, it is imperative for the child neurologist to be aware of recent advances in this aspect of treatable neurometabolic disorders and improve patient care in their setting.
 

Treatable neurometabolic movement disorders
Shekeeb Mohammad

Inborn errors of metabolism (IEM) can present with movement disorders resulting as either an ongoing neurophysiologic impact of metabolic imbalance or as a sequelae of episodic brain injury during metabolic decompensation. Several of these disorders are treatable. Examples of treatable neurometabolic disorders presenting with movement disorders include metal storage disorders such as Wilson disease and inherited hypermanganesemia; neurotransmitter disorders such as GTP cyclohydrolase 1 deficiency, Tyrosine hydroxylase deficiency and cerebral folate deficiency; energy metabolism disorders such as CoQ 10 deficiency, glucose transporter defect, biotin thiamin responsive basal ganglia disease and creatine deficiency syndromes; lysosomal storage disorders such as Gaucher disease and gangliosidoses; and disorders of intermediary metabolism such as biotinidase deficiency, hyperphenylalaninemia and classic homocystinuria.
This session will provide an overview of clinical scenarios presenting with movement disorders that should alert the clinician to consider an IEM. The cases will also be used to provide a framework for considering symptomatic and disease modifying medications for disorders where applicable discussing - Basic principles in treatment of IEMs associated with movement disorders, nuances with dosing and assessing treatment benefits and highlighting novel and emerging treatments.