Neurometabolic disorders

Last updated date: 28-Aug-2023

Originally Written in English

Neurometabolic disorders


Neurometabolic diseases are hereditary abnormalities that affect how the body consumes or generates energy from food. Although the majority of cases occur in children, some can manifest in adults, and a rising percentage of afflicted children survive into adulthood. Certain metabolic diseases can be treated.


Neurometabolic disorders definition

Neurometabolic disorders definition

Neurometabolic diseases are a category of conditions characterized by the absence or failure of an enzyme or vitamin required for a specific chemical reaction in the body, which can result in distinct forms of neurometabolic disorders. A shortage of these important metabolites may interfere with proper brain development.


What are the Signs and Symptoms of Neurometabolic Disorder?

Symptoms of Neurometabolic Disorder

Symptoms of several forms of neurometabolic diseases first develop in newborns or very young children. The symptoms of a child's neurometabolic illness will differ.

The structure of the brain has evolved inappropriately before birth in various neurometabolic diseases. Symptoms of various neurometabolic diseases appear shortly after delivery and at the start of feeding.

Some general symptoms of neurometabolic disorders may include:


Phenylketonuria (PKU)


PKU is an inborn error of metabolism (IEM) caused most commonly by missense mutations in the gene encoding phenylalanine hydroxylase (PAH), which catalyzes the hydroxylation of phenylalanine (Phe) to generate tyrosine (Tyr). Enzyme mutations, such as PAH, are recessive because one working enzyme with the wild-type allele suffices.

PKU pathophysiology is predominantly caused by increased amounts of Phe and its metabolites, such as the keto acid phenylpyruvate. Tyr deficiency may also be detrimental since this amino acid is an essential precursor of three catecholamine neurotransmitters: dopamine, norepinephrine, and adrenaline.

Tyr is also a precursor to melanin, a skin pigment. Tyr deficiency can result in reduced melanin production and pale skin and hair. The specific molecular pathophysiological pathways causing cognitive impairment in PKU are unknown. Increased oxidative stress has emerged as a potential underlying mechanism for PKU neurodegeneration. Other PKU pathophysiological processes include altered neurotransmitter metabolism, reduced brain protein synthesis, and energetics.


Phenylketonuria Symptoms

PKU is often identified at birth by newborn screening tests in the United States, and dietary therapy is initiated in cooperation with a nutritionist and geneticist/metabolism specialist. Mild types of PKU in a baby, on the other hand, might go unnoticed if the mother is released too soon or if the child does not take any protein.

Untreated signs and symptoms of the condition include missed developmental milestones, microcephaly, hypopigmentation, hyperactivity/behavior difficulties, seizures, and a musty stench to skin and urine. Affected children who are detected and treated adequately from birth, on the other hand, are less likely to exhibit symptoms. Long-term care focuses on dietary therapy adherence, blood Phe and Tyr levels monitoring, and screening for any cognitive deficits.


Phenylketonuria diagnosis

PKU is identified in the United States via the state newborn screening program, which uses tandem mass spectrometry (MS/MS) to quantify the Phe/Tyr molar ratio on a filter paper blood spot (from a heal prick). This test is normally performed one or two days after birth. PKU newborns might seem normal at birth, with the first indications showing several months later. Neonates with high blood Phe levels may have a BH4 deficit, which can also cause high Phe levels.


Phenylketonuria Treatment 

Classic PKU, if detected early, can be treated with life-long dietary treatment aimed at maintaining low Phe levels and appropriate Tyr consumption. In general, these dietary strategies are successful at preventing the most severe cognitive damage caused by excessive Phe levels. Nonetheless, nutritional treatment for PKU has been linked to selenium, copper, magnesium, and zinc deficits.

PKU care is complicated, and dietary non-adherence generally develops in adolescence and early adulthood, owing to social difficulties. Aside from a reduced Phe diet, potential medicines for PKU are being researched. 

Because PAH is unstable, enzyme replacement treatment for PKU has proved impossible. Recently, the FDA authorized an enzyme replacement treatment for PKU. In this strategy, a "substitution" enzyme that can reduce Phe levels is given to the PKU patient.

Women of reproductive age with PKU should be counseled about the advantages of careful dietary treatment before and throughout pregnancy. Maternal Phe levels that are too high during pregnancy can induce fetal brain damage and congenital cardiac problems. Elevated Phe during pregnancy can have negative prenatal consequences whether or not the fetus has a PKU mutation.


Wilson disease

Wilson disease

Wilson disease, also known as hepatolenticular degeneration, is an autosomal recessive condition that causes an excess of copper in the body. It predominantly affects the liver and the brain's basal ganglia, although it can also impact other organ systems.

Symptoms are mainly associated with the brain and liver. Vomiting, weakness, ascites, leg swelling, yellowish skin, and itching are all indications of liver disease. Tremors, muscular stiffness, difficulty speaking, personality changes, anxiety, and auditory or visual hallucinations are examples of neurological symptoms.

Wilson disease is an autosomal recessive disorder caused by a mutation in the gene coding for the Wilson disease protein. A copy of the gene from each parent must be inherited for a person to be impacted. Blood tests, urine tests, and a liver biopsy, in addition to a clinical examination, are used to make a diagnosis. Genetic testing may be used to screen afflicted individuals' family members.

The genetic abnormality is located on chromosome 13's long arm (13q), and it has been demonstrated to modify the copper transporting ATP gene in the liver. The majority of Wilson disease patients appear with liver impairment within the first decade of life. Neuropsychiatric symptoms appear in the third/fourth decade of life. Wilson illness is uncommon, yet it is lethal if not diagnosed and treated.


Wilson disease causes

Wilson disease is caused by one of multiple mutations in the ATP7B gene, which is found on chromosome 13 and regulates the protein transporter that excretes excess copper into bile and out of the body. The protein transporter is found in the liver and brain's trans-Golgi network. The liver is the primary route of copper excretion (95 %). This extra copper accumulates first in the liver, then in the blood, and finally in other organ systems.

Excess copper produces free radicals, which cause oxidation of essential proteins and lipids. The mitochondria, nuclei, and peroxisomes are the sites of the first alterations.


Wilson disease symptoms

Patients with Wilson disease may have a favorable family history because it is a heritable condition. Abdominal discomfort, jaundice, weakness, personality changes, depression, migraine headaches, insomnia, seizure, and movement disorder chorea are all possible symptoms. Hemiballismus may have existed in the past.

Neuropsychiatric symptoms, such as asymmetrical tremor, will affect 30-50 percent of individuals. Drooling, ataxia, personality changes, mask-like facies, and clumsiness are all possible signs.

On physical examination, the patient may show hepatosplenomegaly, isolated splenomegaly, or, if the illness has advanced to cirrhosis, chronic liver disease stigmata. A slit-lamp test for Kayser-Fleischer (KF) rings on the cornea may be revealed during an eye exam 

Wilson disease frequently causes skeletal involvement, which mimics early osteoarthritis. Arthropathy often affects the axial bones and spine.

Hemolytic anemia occurs in 10-15% of patients and is caused by red cell lysis caused by the elevated copper content. Wilson disease should be suspected in young patients with reduced liver function, hemolytic anemia, and normal alkaline phosphatase values. Renal symptoms are comparable to those of Fanconi syndrome and urolithiasis.


Wilson disease diagnosis

Order a ceruloplasmin level if you suspect Wilson illness. It will be less than 20 mg/dL (often between 20 and 40 mg/dL). Urinary copper levels will rise over 100 mcg/dL. These two lab results with Kayser-Fleischer rings are typically sufficient for diagnosis, but if another diagnosis is possible, request a liver biopsy for liver copper levels; this is the most reliable test for Wilson disease. It should be noted that low levels of ceruloplasmin can be observed in any protein deficient condition.

A copper level more than 250 mcg/g of dry liver tissue is considered positive. An MRI is useful for determining brain involvement. With increased AST and ALT values, liver function tests are abnormal.

Wilson disease should be suspected if symptoms are consistent with the condition or if a family has the disease. Most exhibited slightly elevated aspartate transaminase, alanine transaminase, and bilirubin levels, as well as mildly abnormal liver function tests. If the liver is severely injured, albumin levels fall due to the inability of damaged liver cells to make this protein; similarly, prothrombin time increases because the liver is not manufacturing clotting components.

Wilson-related acute liver failure patients had decreased alkaline phosphatase levels. If there are neurological symptoms, an MRI of the brain in the T2 sequence may demonstrate hyperintensities in the basal ganglia. MRI may reveal the distinctive "face of the gigantic panda" pattern.

The ECG may show signs of ventricular hypertrophy, arrhythmias, and non-specific alterations in T waves and ST segments. Wilson illness is suggested by the existence of Kayser Fleischer rings in the context of neuropsychiatric symptoms.

Although there is no entirely valid test for Wilson disease, levels of ceruloplasmin and copper in the blood, as well as copper excreted in urine during a 24-hour period, are used to estimate the quantity of copper in the body. A liver biopsy is the gold standard.


Wilson disease Treatment 

Copper chelation therapy with penicillamine and trientine is the standard treatment for Wilson disease. Because it has fewer adverse effects, trientine is chosen. Oral zinc may also be administered since it competes with copper for absorption at the metallic ion transporter. It is critical to inform the patient about the negative effects of continuous chelation treatment, which can exacerbate symptoms. D-penicillamine is safe to use throughout pregnancy and poses no harm to the baby.

Transjugular intrahepatic portosystemic shunt (TIPS) can be used to treat recurrent variceal bleed if the patient develops liver cirrhosis and its accompanying complications. Liver transplantation is a curative procedure.

Baclofen, anticholinergics (trihexyphenidyl), GABA antagonists, and levodopa may be used to treat muscular stiffness, spasticity, and parkinsonian characteristics.

liver transplantation appeared to be useful in alleviating neurological dysfunction in certain patients who were not responding satisfactorily to conventional treatment. A low-copper diet is advised, with mushrooms, chocolate, almonds, dried fruit, liver, and shellfish being avoided.

In the neurologic form of the condition, physiotherapy and occupational therapy are useful. The copper-chelating treatment can take up to six months to begin functioning, and these therapies can help people cope with ataxia, dystonia, and tremors, as well as avoid contractures caused by dystonia.


Gaucher disease

Gaucher disease

Gaucher disease is an autosomal recessive inborn metabolic mistake caused by glucocerebrosidase (GBA1) gene mutations. The enzyme GBA1 cleaves the beta-glucosidic bond of glucocerebroside lipids. Inborn metabolic errors are especially significant in pediatrics because they frequently (but not always) manifest during the neonatal stage of infancy.

Gaucher disease is classified into five types: type 1, type 2, type 3, perinatal fatal, and cardiovascular. The most severe type is perinatal fatal, and difficulties can begin before delivery or in early infancy.

Knowing the primary signs of any inborn metabolic abnormality is essential for reaching a diagnosis. Inborn metabolic mistakes are caused mostly by a lack (or inadequate amounts) of particular enzymes:

  1. Convert fat or carbohydrates to energy or to;
  2. Breakdown amino acids or other metabolites, allowing them to accumulate and become toxic if not treated. 

Gaucher disease is an inborn metabolic mistake caused by the buildup of glucocerebroside lipids. It is the leading cause of lysosomal storage disorders. Lysosomes are subcellular organelles that are in charge of the normal turnover of cell components. Toxic accumulation inborn errors of metabolism are classified into three types: localized toxicity, systemic toxicity, and a mix of the two. 


Gaucher disease symptoms 

Gaucher disease symptoms

Gaucher illness can manifest in a variety of ways, depending on the underlying cause. The following are examples of common presenting symptoms:

  • Painless hepatomegaly and splenomegaly
  • Hypersplenism and pancytopenia
  • Severe joint pains, most frequently affecting hips and knees.
  • Impaired olfaction and cognition (Type I)
  • Serious convulsions, hypertonia, intellectual disability, and apnea (Type II)
  • Myoclonus, seizures, dementia, and ocular muscle apraxia (Type III)
  • Parkinsonism
  • Osteoporosis
  • Yellowish-brown skin pigmentation

Gaucher disease is diagnosed by detecting a low GBA1 enzyme level in peripheral blood leukocytes as well as the presence of mutant alleles in the GBA1 gene. Despite the fact that Gaucher illness may be diagnosed with just a blood sample, some people are subjected to needless invasive bone marrow or liver biopsy before receiving a precise diagnosis.

Such problems can be avoided if physicians are aware of the signs and symptoms of Gaucher illness. Furthermore, many individuals with an enlarged liver or spleen are informed they may have cancer before an official diagnosis is obtained.


Gaucher disease Diagnosis

Gaucher disease Diagnosis

Laboratory Studies

CBC Count

  • CBC and platelet count will access the degree of cytopenia.

Liver Function Enzyme Testing

  • Mild elevations in liver enzyme levels are usual; nevertheless, the presence of jaundice or aberrant hepatocellular synthesis function warrants additional investigation.


  • Regular monitoring should be performed.

Enzyme Activity

  • Diagnosis is confirmed through measurement of glucocerebrosidase activity in peripheral blood leukocytes. Less than 15% of mean normal activity is diagnostic.

Associated Marker Testing

  • The levels of angiotensin-converting enzyme, total acid phosphatase, and ferritin are frequently increased. These levels may return to normal after therapy.
  • Except for the 10% of the population who are deficient in this protein, monitoring the chitotriosidase enzyme is beneficial.
  • Monitoring glucosylsphingosine levels may be beneficial because the level has been proven to correspond with medication response.



  • Ultrasonography - may reveal abdominal organomegaly.
  • MRI - may be useful in revealing early skeletal involvement (avascular necrosis, spinal degradation, and degree of bone marrow infiltration.
  • Radiography - may reveal skeletal manifestations and pulmonary involvement.
  • Dual-energy x-ray absorptiometry - may evaluate osteopenia and bone crises.
  • Echocardiograms are helpful in evaluating the possibility of pulmonary hypertension.


Gaucher disease Treatment 

Gaucher disease treatment is divided into two categories: enzyme replacement therapy and substrate reduction therapy. Enzyme replacement treatment, in general, involves the administration of an intravenous infusion containing the enzyme that is weak or missing in the body.

Because the blood-brain barrier prevents enzyme replacement therapy from replacing an enzyme missing in the brain, it is ineffective for addressing the central nervous system disorders associated with type 2 and 3 Gaucher disease. Enzyme replacement treatment can assist with the "non-brain" symptoms of type 3 Gaucher disease, such as enlarged organs and skeletal problems.

Enzyme replacement treatment does not cure the underlying genetic problem; it merely relieves the indications, symptoms, and long-term harm caused by toxin buildup. Furthermore, antibodies to the replacement enzyme can be developed.

Substrate reduction treatment is an orally delivered small-molecule medication (not a protein) that works differently from enzyme replacement therapy. The purpose of substrate reduction treatment is to lower the levels of a substrate such that hazardous buildup of the substrate's subsequent degradative product is reduced to a clinically less toxic level.


Maple Syrup Urine Disease (MSUD)

Maple Syrup Urine Disease

In 1954, Menkes' neurodegenerative illness was initially identified as maple syrup urine disease (MSUD). It's a metabolic abnormality caused by aberrant activity of the branched-chain alpha-ketoacid dehydrogenase (BCKAD) complex. This complex is in charge of breaking down branched-chain amino acids:

  • Leucine
  • Isoleucine
  • Valine

It often presents as failure to grow, missed developmental milestones, feeding problems, and a maple syrup odor in the urine or cerumen during the newborn period. Close metabolic monitoring and dietary restriction of branched-chain amino acids are used in treatment. If untreated, severe cerebral damage and metabolic disaster occur. If treatment is started early, good clinical outcomes can be predicted.


Treatment of Maple Syrup Urine Disease

Treatment of Maple Syrup Urine Disease

The treatment of classic, intermediate, intermittent, and thiamine-responsive MSUD has three chief components: 

  1. Lifelong therapy to maintain an acceptable diet;
  2. Life-long maintenance of normal metabolic conditions including the levels of the BCAAs in the body; 
  3. Immediate medical intervention for metabolic crises.

Individuals with MSUD must follow a protein-restricted diet that limits their intake of branched-chain amino acids. To ensure appropriate growth and development, protein restriction should begin as soon as feasible after delivery. There are synthetic (artificial) formulations available that give all of the nutrients required for optimal growth and development but lack leucine, isoleucine, and valine.

Diet management is a continual balancing act between providing adequate food, protein, and BCAAs to support normal growth and development on the one hand and attempting to keep the patient's condition and biochemistry within therapeutic ranges on the other. Limiting the quantity of leucine in the diet is very crucial. The three amino acids are all necessary nutrients.

They are introduced to the diet in tiny doses based on their plasma levels. The quantity of leucine, isoleucine, and valine that a kid can tolerate is determined by residual enzyme activity. Affected youngsters must be examined on a frequent basis to ensure that their food is appropriate and that their amino acid levels are within within acceptable ranges.

Some doctors prescribe a thiamine treatment trial to see if an afflicted person is thiamine-responsive. However, no person with MSUD has ever been treated only with thiamine. Other forms of therapy include symptomatic and supportive. Affected individuals and their families should seek genetic counseling.



Neurometabolic diseases are a category of ailments that cause difficulties with metabolism as well as brain function, and can result in uncontrolled seizures, aberrant movements, or the loss of developmental milestones. Mitochrondial and demyelinating diseases are examples of these.