What is Neurometabolic Disorders (NMD)?
Chemistry is the foundation of life, which is why biochemical or metabolic errors are of great significance. There are many known NMDs, approximately 600 genetic conditions that can result in NMDs. Individually, they are rare, but collectively, they are quite common.
They are due to brain dysfunction caused by deranged cell metabolism, i.e., accumulation of waste products or reduced production of essential chemicals, such as amino acids, organic acids, carbohydrates, fatty acids, vitamins, neurotransmitters, and lipoproteins.
What are the characteristics of Neurometabolic disorders?
- Symptom-free interval
- Progressive or step-wise evolution of symptoms
- Unexplained symptoms; developmental delay; low tone/ hypotonia; anorexia; vomiting
- Acute events
- Recurrent coma
- Difficult to treat symptoms
- Worsened by fever/ intercurrent illnesses, fasting trauma
- Consanguinity
- Family history, especially unexplained illness
What are the important signs and symptoms of Neurometabolic disorders?
Key features:
1. Age of onset
- Acute symptoms during neonatal period
- Early onset infantile or late infantile progressive encephalopathy
- Childhood and adolescent disorders
2. Presentation
- Acute encephalopathy (brain dysfunction), e.g. organic acidaemia, urea cycle defect
- Developmental regression, e.g. grey or white matter diseases
- Visual loss, e.g. NCL/ Batten’s disease
- Myopathy, e.g. Mitochondrial disorders
- Neuropathy, e.g. Peroxisomal disorders, INAD
- Movement disordfers/ ataxia, e.g. neurotransmitters disorders
- Seizures, e.g. grey or white matter diseases, Progressive Myoclonic Epilepsy, mitochondrial disorders.
- Behavioural/ Cognitive Disturbance, e.g. Lysosomal disorders, white matter disorders
3. Examination Findings
- Macrocephaly
- Retinal abnormalities
- Dementia
- Psychiatric
- Spasticity
- Movement disorders (dystonia, chorea, ataxia)
- Unexplained focal signs
- Facial appearance/ dysmorphism
- Multisystem involvement
How is Neurometabolic disorder in Children Diagnosed?
Diagnosing neurometabolic disorders (NMD) in children can be challenging, and it involves a thorough evaluation by a paediatric neurologist, including a detailed medical history, physical examination, neurological assessment, and neuroimaging, such as MRI brain scan or MRS (MR Spectroscopy, a special MRI brain analysing the signals emitting from brain cell chemicals). Fluid collected from the lumbar puncture (LP), i.e. Cerebrospinal Fluid (CSF), urine and blood will be analysed for special chemical/ mineral levels.
MRI brain is recommended as it is more sensitive in picking up abnormal changes than CT head. Electroencephalogram (EEG) tests maybe requested to analyse your child’s brain wave signals/ pattern.
Genetic testing for neurometabolic disorders, or tissue biopsy, such as muscle or skin biopsies, may be suggested by Dr Yeo or your paediatric neurologist.
When dealing with neurometabolic disorders, it can be challenging to decide whether to conduct testing or not, especially since many of these conditions are progressive. One crucial factor to consider is whether the disorder is static or progressive. If we are unsure about the answer, it may be necessary to proceed with investigations as if the disorder were progressive.
The followings are a list of common neurometabolic tests which are often used in the diagnosis of neurological disorders in children:
| Urine test | Indications |
|---|---|
|
Urine Organic Acids |
Developmental delay, learning disability, macrocephaly, movement disorders, ’cerebral palsy’, encephalopathy with or without epileptic seizures, myelopathy |
|
Urine Copper |
Movement disorders, behaviour disorder with or without liver dysfunction |
|
Urine Catecholamines |
Acute or subacute cerebellar ataxia, myoclonus, opsoclonus; early onset movement disorder with dystonia and oculogyric crisis; neonatal hypothermia and failure to thrive |
|
Urine GAG (glycosaminoglycans) |
Learning disability, coarse facies, corneal clouding, speech impairment, behavioural impairment. |
| Blood test | Indications |
|---|---|
|
Acylcarnitine/ carnitine profile |
Acute encephalopathy, Acute myopathy, rhabdomyolysis, unexplained hyperCKaemia |
|
Alpha-fetoprotein |
Ataxic ‘CP’, oculomotor apraxia |
|
Amino Acids |
Learning disability, hypotonia, early onset epilepsy, acute encephalopathy, intermittent ataxia, movement disorders, stroke |
|
Ammonia |
Early onset seizures, acute encephalopathy, stroke, vomiting-headache-impaired consciousness complex, ataxia |
|
Caeruloplasmin |
- Movement disorders, behaviour disorder with or without liver dysfunction - hypotonia, seizures, steely hair |
|
Calcium |
- Seizures, learning disability, movement disorders - developmental delay/ elfin facies |
|
Cholesterol |
Developmental delay, retinopathy, deafness, skeletal dysplasia, ataxia, spinocerebellar ataxia |
|
Copper |
- Movement disorders, behaviour disorder with or without liver dysfunction - hypotonia, seizures, steely hair |
|
CK |
Speech delay, toe walking, muscle weakness |
|
Creatinine |
Learning disability, seizures, movement disorders |
|
Electrolytes (Sodium, potassium, bicarbonate) |
Acute illness, intermittent weakness |
|
Ferritin |
Iron deficiency, restless leg syndrome, infection |
|
Glucose |
Reduced level of consciousness, seizures |
|
Lactate |
Encephalopathy, suspected mitochondrial disorders |
|
Magnesium/ Phosphate |
Neonatal seizures |
|
Prolactin |
Movement disorders, unexplained ‘seizures’ |
|
Thyroid function tests/ fT3 |
Thyroid diseases, encephalopathy, movement disorders |
|
Liver function tests |
- Developmental delay, hypotonia - Congenital infection/ congenital infection like disorder - Suspected mitochondrial disorders |
|
Uric Acid |
Early movement disorder with developmental delay |
|
Vitamin A |
Loss of vision in autism |
|
Vitamin B12 |
Developmental delay, seizures, movement disorders |
|
Vitamin E |
Developmental delay, retinal defects, deafness, ataxia |
| CSF test | Indications |
|---|---|
|
Amino acids |
Learning disability, hypotonia, early onset epilepsy, acute encephalopathy, intermittent ataxia, movement disorders, stroke |
|
Glucose |
Epilepsy, developmental delay, ataxia, movement disorders |
|
Lactate |
Suspected mitochondrial disorders |
|
Neurotransmitters |
Movement disorders, suspected inflammatory CNS disorder |
Why Neurometabolic disorder can be missed in children or adults?
- Wrongly attributed a child’s fever and confusion to an urinary tract infection (based on urine dipstick) or chest infection (based on a few chest signs), without strong evidence.
- Ignoring a caregiver’s complaint that a child is ‘not quite right’, sleepy, or lethargic.
- Wrongly attributing clouding of consciousness to drugs or alcohol, without good evidence.
- Failure to properly investigate a child with an unexplained illness or seizure
- Misleading investigation results?
- Targeted investigations vs ‘metabolic screen’?
What is the treatment for Neurometabolic disorders?
Most NMD do not have a cure. However, there are many treatments which can manage and control symptoms and help improve life expectancy and quality of life for children with NMD.
Some children will require long-term follow-up and support from paediatric neurologists and allied health professionals. Some patients with NMD will have to adhere to special diets.
With advances in medical technology and genetics, specific drug treatments, such as enzyme replacement therapy (ERT) or gene therapy, are available for certain NMD.
References
Dr Yeo’s recent peer-group review journal publications and abstracts regarding Neurometabolic disorders:
Leow, XYJ & Tan, JTC & Yeo, Tong & Wong, Kenneth & Mahadev, Arjandas & Ang, Bixia & Vasanwala, Rashida & Ng, Zhi Min. (2021). Evaluation of risk factors associated with fragility fractures and recommendations to optimise bone health in children with long-term neurological condition. Singapore Medical Journal. 64. 10.11622/smedj.2021124.
Hamilton R, Yeo TH, et al. Sensitivity and specificity of the light-adapted ERG in suspected neuronal ceroid lipofuscinoses (NCLs). Documenta Ophthalmologica, Aug 2016;133 (1S).
Yeo TH, Vassallo G, Judge M, Laycock N, Kelsey A, Crow YJ. Infantile neurological Degos disease. Eur J Paediatr Neurol. 2011 Mar;15(2):167-70.
Yeo TH, De Goede C, Crow Y. Biotin non-responsive familial infantile bilateral striatal necrosis associated with primary Influenzae A infection. Eur J Paediatr Neurol. 2011 May:15(1):S117-S118.
Yeo TH, et al. Coexistence of Krabbe’s disease and multiple chromosomal abnormalities: a case report. Poster presentation. Eur J Paediatr Neurol. Eur J Paediatr Neurol. 2011 May:15(1): S52-S53.
Yeo TH, et al. The value of CT brain in undiagnosed neurological disorders. Eur J Paediatr Neurol. 2009 Sept: 13(1):S124.
