Browsing Pathways

Adrenoleukodystrophy (ALD) is an X-linked recessive transmission disease. Central nervous system signs and symptoms have been consistently more prominent than signs of adrenal involvement. Behavioral changes are the most common initial finding and range from aggressive outbursts to withdrawal. Such behavior is generally accompanied by a gradually failing memory and poor school performance. Loss of vision is an early finding in some patients and is a prominent feature at some stage in most affected individuals. The initial visual loss appears as homonomous hemianopsia in some individuals and is usually associated with intact pupillary reflexes. Optic atrophy is less common as an initial finding but eventually develops in almost all cases. Gait disturbance is also an early finding and as is stiff-legged, unsteady and accompanied by hyperreflexia. In almost all cases there is spastic quadraplegia and a variable degree of decorticate posturing. Hearing loss, dysarthria and dysphagia develop at about the same time as gait disturbance. Seizures are a typical symptom in many affected individuals in the the end stages of the disease progression.

Trifunctional protein deficiency is a condition caused by mutations in the genes HADHA and HADHB. The enzyme affected is required to metabolize long-chain fatty acids, which makes a patients ability to convert fats to energy very difficult. This is exacerbated by periods without food. The symptoms associated with this disorder differ depending on when they appear in a patient. In infancy, symptoms would include lethargy, hypoglycaemia and hypotonia. Infants are also at higher risk for sudden death and heart problems. Later onset trifunctional protein deficiency symptoms also include hypotonia, but also include breakdown of muscle tissue and peripheral neuropathy. Treatment includes a low-fat, high-carbohydrate diet and avoiding fasting, as this can induce symptoms of this condition.

Medium-chain acyl-CoA dehydrogenase deficiency, which is also known as MCADD, is a rare inherited inborn error of metabolism (IEM) medium-chain fatty acid metabolism. The estimated birth prevalence of MCADD is between 1 in 4 900 to 1 in 27 000 in Caucasian populations and is highest in Northern European individuals. Worldwide birth prevalence is 1 in 14 600. MCADD is an autosomal recessive disorder associated with a mutation in the enzyme medium-chain acyl-CoA dehydrogenase (MCAD). MCAD is an enzyme that catalyzes the initial step in each cycle of medium-chain fatty acid beta-oxidation in the mitochondria of cells. MCAD’s action results in the introduction of a trans-double-bond between C2 and C3 of the acyl-CoA thioester substrate. Defects in MCAD leads to the accumulation of medium-chain fatty acids in the blood, lowering the blood's pH and causing acidosis. Likewise, individuals with MCADD have difficulty metabolizing fats. As a result, MCADD is characterized by intolerance to prolonged fasting, recurrent episodes of hypoglycemic coma with medium-chain aciduria, impaired ketogenesis, and low plasma and tissue carnitine levels. Intolerance to fasting and hypoglycemia result from the inability to gain energy and make sugar from fat stores, which is how most excess energy from food is stored. It is rare for the signs and symptoms of MCADD to first appear during adulthood. Typically, they manifest during infancy or early childhood and can include lethargy, hypoglycemia, and vomiting. MCAD-deficient individuals are at risk for breathing difficulties, liver problems, seizures, brain damage, coma, and sudden death. Fasting or illnesses (e.g. viral infections) can trigger related problems. Infants and young children with MCADD need to eat frequently to prevent hypoglycemia or a metabolic crisis. MCADD is occasionally mistaken for Reye syndrome, a severe disorder that may manifest in children during apparent recovery from viral infections such as flu or chickenpox. The majority of Reye syndrome cases are associated with aspirin use during these viral infections.

Carnitine palmitoyltransferase II deficiency, which is also known as CPT II deficiency, is an inherited inborn error of metabolism (IEM) of fatty acid oxidation leading to muscle weakness. It is the most common inherited disorder of lipid metabolism affecting the skeletal muscle of adults. It is an autosomal recessive disorder associated with a mutation in the enzyme carnitine palmitoyltransferase II. Carnitine palmitoyltransferase II (CPT2) is a peripheral inner mitochondrial membrane protein found in all tissues that oxidize fatty acids. It catalyzes the transesterification of palmitoylcarnitine back into palmitoyl-CoA which is a substrate for beta-oxidation inside the mitochondrial matrix. CPT2 is responsible for the formation of acylcarnitines by catalyzing the transfer of the acyl group of a long-chain fatty acyl-CoA from CoA to carnitine. Carnitine, a natural substance acquired mostly through the diet, is used by cells to process fats and produce energy. Deficiencies or mutations in the CPT2 gene lead to disorders of long-chain fatty acid oxidation. There are three forms of CPT II deficiency: (1) lethal neonatal form, (2) severe infantile hepatocardiomuscular form, and (3) the myopathic form. More than 300 CPT II deficiency cases have been described with the myopathic form being the most common (myopathic form: 86%, severe infantile form: 8%, neonatal form: 6% of cases). The myopathic form is usually mild and can manifest from infancy to adulthood. The infantile and neonatal forms are severe multisystemic diseases characterized by liver failure with hypoketotic hypoglycemia, cardiomyopathy, seizures, and early death. The adult-onset myopathic form is characterized by exercise-induced muscle pain and weakness, sometimes associated with myoglobinuria. The most common cause of hereditary myoglobinuria is the myopathic form of CPT II deficiency and affects men more than women.

Very long-chain acyl-CoA dehydrogenase deficiency (VLCAD), also called ACADL and VLCAD, is a rare inborn error of metabolism (IEM) and autosomal recessive disorder, which is caused by a defective very long-chain specific acyl-CoA dehydrogenase. Very long-chain specific acyl-CoA dehydrogenase breakdown certain fats to energy. This disorder is characterized by a large accumulation of fatty acids such as L-Palmitoylcarnitine in the mitochondria. Symptoms of the disorder include muscle weakness, lethargy (lack of energy) and hypoglycemia (low blood sugar). Treatment with diet modifications such as consuming supplemental calories is suggested. It is estimated that very long-chain acyl-CoA dehydrogenase deficiency affects 1 in 40,000 to 120,000 individuals.

Long Chain Acyl CoA Dehydrogenase Deficiency (LCADD) is a rare disorder that is inherited through an autosomal recessive trait, and prevents the body from properly metabolizing very long chain fatty acids. This disorder occurs in the mitochondria, where the metabolization of fatty acids takes place. Early-onset LCADD patients usually begin to exhibit symptoms just days or weeks after birth. Hypoglycemia, lethargy and irritability are symptoms associated with this disorder. Patients will also be at risk for hypertrophic cardiomyopathy and other heart conditions from age two months to two years. It can be diagnosed through a research of family history and generally a urine analysis will reveal that the patient has reduced of absent ketone bodies. To help control acute episodes, treatment includes maintaining a high carbohydrate and low fat diet, and avoiding fasting for more than 12 hours.

Carnitine palmitoyltransferase I deficiency, which is also known as CPT I deficiency, is a very rare inherited inborn error of metabolism (IEM) leading to muscle weakness. Fewer than 50 people have been identified with this condition. It is an autosomal recessive disorder associated with a mutation in the enzyme carnitine palmitoyltransferase I. Carnitine palmitoyltransferase I (CPT1) is also known as carnitine acyltransferase I (CAT1), CoA:carnitine acyl transferase (CCAT), or palmitoylCoA transferase I. CPT I is a mitochondrial enzyme. It is responsible for the formation of acylcarnitines by catalyzing the transfer of the acyl group of a long-chain fatty acyl-CoA from CoA to carnitine. Carnitine, a natural substance acquired mostly through the diet, is used by cells to process fats and produce energy. Defects in CPT I prevents the body from using certain fats for energy, particularly during periods of fasting. Affected individuals often have increased carnitine levels along with low blood sugar (hypoglycemia) and a low level of ketones (hypoketosis), which are produced during fat metabolism as an energy source. Together these signs are termed hypoketotic hypoglycemia. The condition's severity varies greatly among affected individuals and many of the signs and symptoms manifest during early childhood. People with CPT I deficiency can also have an enlarged liver (hepatomegaly) and liver malfunction. CPT I deficienct individuals are at risk for liver failure, nervous system damage, seizures, coma, and sudden death. Affected individuals should eat a high-carbohydrate, low-fat diet and avoid fasting.

Short Chain Acyl CoA Dehydrogenase Deficiency (SCAD Deficiency) is caused by mutation in the gene encoding short-chain acyl-CoA dehydrogenase, an enzyme which normally breaks down short chain fatty acids. SCADD causes accumulation of ammonia in blood; butyrylcarnitine(C4) in plasma; adipic acid, butyrylglycine, ethylmalonic acid; hexanoylglycine and methylsuccinic acid in urine. Symptoms include hypoglycemia, hypotonia, microcephaly, failure to thrive, lactic acidosis, peripheral neuropathy, and vomiting.

Glutaric Aciduria Type 1 is a rare autosomal recessive disease caused by a mutation in the GCDH which codes for glutaryl-CoA dehydrogenase. A deficiency in this enzyme results in accumulation of 3-hydroxybutyric acid, 3-hydroxyglutaric acid, glutaconic acid, glutaric acid, and ketone bodies in urine. Symptoms include encephalopathy, grimacing, dystonia, metabolic acidosis, and hygroma. Treatment includes a low-protein diet, L-carnitine, riboflavin, and anticonvulsants.

Ethylmalonic Encephalopathy (Epema Syndrome; EE) is a rare autosomal recessive disorder caused by a mutation in the ETHE1 gene which codes for protein ETHE1. A deficiency of this protein inhibits proper energy production in mitochondria and a deficiency in cytochrome c oxidase. This results in accumulation of 2-methylbutyrylglycine, N-butyrylglycine, isobutyrylglycine, isovalerylglycine, and methylsuccinic acid in urine. Concentrations of L-carnitine are reduced in plasma. Symptoms, which present at birth, include peripheral neuropathy, seizures, microcephaly, and hypotonia lead to premature death. Treatment includes riboflavin and L-carnitine.