What is Neurometabolic Disorders (NMD)?
Chemistry is the foundation of life, which is why biochemical or metabolic disorders are of great significance. There are approximately 600 known genetic conditions that can result in metabolic disorders (MD). While each condition is rare individually, collectively, they are quite common.
These disorders arise from brain dysfunction caused by issues in cell metabolism. This can lead to the accumulation of waste products or a reduced production of essential substances, such as amino acids, organic acids, carbohydrates, fatty acids, vitamins, neurotransmitters, and lipoproteins.
What are the Characteristics of Metabolic 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?
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 Metabolic Disorders in Children Diagnosed?
Diagnosing Metabolic Disorders (MD) in children presents significant challenges, necessitating a comprehensive evaluation by a paediatric neurologist. This process involves a meticulous medical history, thorough physical examination, detailed neurological assessment, and advanced neuroimaging techniques such as an MRI brain scan or MRS (Magnetic Resonance Spectroscopy), which meticulously analyses the chemical signals emitted by brain cells. In addition, cerebrospinal fluid (CSF) collected through a lumbar puncture (LP), alongside urine and blood samples, will be thoroughly examined for specific chemical and mineral levels.
The MRI brain scan stands out as the preferred method, as it is far more sensitive in detecting abnormal changes than a CT scan. Additionally, an electroencephalogram (EEG) may be utilised to scrutinise your child’s brain wave patterns, providing critical insights into their neurological function.
Furthermore, genetic testing for metabolic disorders or tissue biopsies, whether muscle or skin, might be strongly recommended by Dr. Yeo or your paediatric neurologist, depending on the specific case.
Navigating the complexities of metabolic disorders can make the decision to conduct further testing particularly daunting, especially given the progressive nature of many of these conditions. A vital consideration is whether the disorder is static or progressive. In situations where there is any uncertainty, it is crucial to proceed with investigations as if the disorder were progressive, ensuring that no potential course of action is overlooked.
The following list outlines common metabolic tests that serve as powerful tools in diagnosing neurological disorders in children, underscoring the importance of thorough assessment and timely intervention:
| 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 Metabolic Disorders 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 Metabolic 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.
If you have any further questions, you can schedule an appointment today with Dr Yeo.
If you have any further questions, you can schedule an appointment today with Dr Yeo.
References
Dr Yeo’s recent peer-group review journal publications and abstracts regarding Neurometabolic disorders:
Cheng, Duo-Tong, Yeo, Tong Hong, Seng, Michaela Su-Fern, Teoh, Oon Hoe, Lee, Sumin; Koh, Ai Ling. Genomic sequencing: ending the diagnostic odyssey for a child with microcephaly and dystonia with a perioperative challenge. Singapore Medical Journal ():10.4103/singaporemedj.SMJ-2023-134, June 28, 2024. | DOI: 10.4103/singaporemedj.SMJ-2023-134
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.
