Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder which results from a deficiency in enzymes involved in cortisol biosynthesis. Approximately 95% of cases of CAH are caused by defects in the CYP21A2 gene, which leads to a deficiency of the steroid 21-hydroxylating enzyme. Approximately 1 in 12 individuals is a carrier of CAH. Symptoms of CAH vary based on the form of CAH, the age of diagnosis, and the sex of the patient. The classic presentation of CAH includes ambiguous genitalia, precocious puberty, and excessive facial hair, and in severe cases includes inadequate adrenal aldosterone secretion that can result in fatal salt-wasting crises. The milder form, non-classic CAH, is not typically detected through newborn screening and is often not diagnosed until later in childhood or adulthood. Treatment for CAH usually includes steroids to replace the low hormones. The long-term prognosis for individuals with CAH is usually favorable, and with lifelong treatment, affected individuals typically have good health and normal lifespans.
Zellweger syndrome spectrum (PEX1-related) is an autosomal recessive disease of peroxisome biogenesis. It is comprised of three diseases that make up a continuum of severity, from the most severe, known as Zellweger syndrome, to neonatal adrenoleukodystrophy, to infantile Refsum disease, which is the mildest. Zellweger syndrome is characterized by demyelination of structures in the brain leading to leukodystrophy, resulting in seizures and vision loss. Clinical features also include dysmorphic features, hypotonia, cardiac problems, and dysfunction of the liver and kidneys. Death typically occurs in the first year of life. Neonatal adrenoleukodystrophy and infantile Refsum disease share many overlapping features. Onset of symptoms may be in infancy, or may be noticed later in childhood. Features include developmental delay and loss of vision and hearing; some children present with bleeding in the brain. The severity and course of the disease can vary between individuals; some may learn to walk and talk, and rarely, patients may survive until adulthood; others never walk or talk. Many patients do not survive childhood. Symptoms tend to progress in severity over the course of the patients life.
Myoneurogastrointestinal encephalopathy is an autosomal recessive disorder caused by pathogenic variants in the gene TYMP. While this disease has been reported in patients of different ethnicities, a founder effect has been identified in the Sephardic Jewish population from Iran. Onset of symptoms is usually in adolescence or early adulthood; some patients do not show symptoms until middle age. Clinical features include progressive gastrointestinal dysmotility, which is associated with weight loss, pain and distension of the abdomen, reflux and difficulty eating. Weakness of the eye muscles develops, resulting in eyelid drooping and difficulty moves the eyes. Pain and tingling of the lower extremities, as well as muscle weakness, can also occur. Progressive worsening of the symptoms results in a shortened life expectancy; the average age of death is 38 years. No genotype-phenotype correlation has been reported, and therefore the age of onset and the severity of the disease cannot be predicted based on genotype.
Neuronal ceroid-lipofuscinosis (TPP1-related) is an autosomal recessive neurodegenerative disorder that is caused by pathogenic variants in the gene TPP1. While it is found in different ethnicities around the world, it is more prevalent in individuals from Newfoundland, Canada due to the presence of a founder mutation. Most TPP1-caused neuronal ceroid-lipofuscinosis results in the late infantile form, in which symptoms begin between 2 and 4 years of age. Clinical features include progressive visual loss and neurologic symptoms, including seizures, ataxia, cerebral atrophy, and developmental regression. Affected individuals do not survive beyond adolescence. Rarely, patients may be diagnosed with a later-onset form. It is not currently possible to predict the age of disease onset based on the patients genotype.
Niemann-Pick disease, type C (NPC1-related) is an autosomal recessive, pan-ethnic neurodegenerative disorder that is caused by pathogenic variants in the gene NPC1. The classic presentation includes spastic ataxia and seizures that begin between the ages of 2 and 4, often after a period of normal development. Progressive deterioration leads to the loss of previously learned speech, dystonia that eventually prevents oral feeding, and dementia. Most patients die in adolescence. Some patients may present in infancy with liver and lung problems, many of whom die in infancy. Occasionally, patients can present in adolescence or adulthood with neurologic manifestations. Several specific variants may be associated with the development of either the severe infantile or typical juvenile form, but some variants may not be associated with a known genotype-phenotype correlation.
Niemann-Pick disease (SMPD1-related) is an autosomal recessive neurodegenerative disorder caused by pathogenic variants in the gene SMPD1. While it has been reported in patients of various ethnicities, it is more common in individuals of Ashkenazi Jewish descent due to the presence of a founder mutation. Two different phenotypes have been associated with pathogenic variants in this gene, known as Niemann-Pick disease, types A and B. Type A, which is the most severe, manifests in infancy with an enlarged liver and spleen and failure to thrive resulting from feeding difficulties. Patients develop hypotonia and severe developmental delay and intellectual ability. As the brain disease progresses, patients develop spasticity and rigidity of limbs. Death usually occurs at ages 2 to 3. Type B does not involve major neurological manifestations, unlike type A. Features include frequent respiratory infections and breathing difficulties, as well as enlarged organs including the liver, spleen and kidney. A subset of patients may have intellectual disability or psychiatric disorders. Onset is in infancy or childhood, but many patients survive into adulthood. Several specific variants have been associated with either type A or type B. The pathogenic variant that is commonly found in the Ashkenazi Jewish population usually results in type A disease.
Niemann-Pick disease, type C (NPC2-related) is an autosomal recessive, pan-ethnic neurodegenerative disorder that is caused by pathogenic variants in the gene NPC2. The classic presentation includes spastic ataxia and seizures that begin between the ages of 2 and 4, often after a period of normal development. Progressive deterioration leads to the loss of previously learned speech, dystonia that eventually prevents oral feeding, and dementia. Most patients die in adolescence. Some patients may present in infancy with liver and lung problems, many of whom die in infancy. Occasionally, patients can present in adolescence or adulthood with neurologic manifestations. Several specific variants may be associated with the development of either the severe infantile or typical juvenile form, but some variants may not be associated with a known genotype-phenotype correlation.
Propionic acidemia (PCCB-related) is an autosomal recessive, pan-ethnic disease caused by pathogenic variants in the gene PCCB. Age of onset is usually infantile, but it may occur later in childhood or adolescence. In the infantile-onset disease, babies are born healthy but within several days they begin to vomit frequently and become lethargic. This metabolic crisis can lead to coma and death if not detected and treated, but even with treatment most babies develop brain damage. Metabolic crises are likely to occur during periods where the infant is sick or develops an infection. The later-onset form resembles the infantile form in many ways, but occurs after a period of relatively normal development. Symptoms of this form include developmental regression and cardiomyopathy. As patients with propionic aciduria grow, they may have intellectual disability and seizures, as well as cardiomyopathy and pancreatitis. Some patients also have vision and/or hearing loss. Most patients need to be fed by nasogastric tubes or gastrostomy. Null alleles and specific missense variants are associated with early-onset and severe disease, whereas other missense variants may retain some enzymatic function and result in a milder disease. Life expectancy is variable; for patients diagnosed before metabolic crisis, preventative treatment often results in a better outcome. Otherwise, life expectancy is limited and some patients die in childhood.
Pyruvate dehydrogenase E1-alpha deficiency is a pan-ethnic disorder caused by pathogenic variants in the gene PDHA1. It is inherited in an X-linked dominant manner and both males and females are affected, although males may be more severely affected than females. Clinical features usually include neonatal lactic acidosis and hypotonia. Some patients have seizures, brainstem dysfunction, and/or facial dysmorphism. Many male patients die in infancy or early childhood, although some may survive to adolescence. Female patients generally have a longer period of survival. Currently, it is not possible to predict the severity of disease from the patients genotype.
Pyruvate dehydrogenase E1-beta deficiency is a pan-ethnic disorder caused by pathogenic variants in the gene PDHB. Age of onset is usually in childhood, but has been reported to occur sometimes in infancy or adolescence. Clinical features vary between patients, but have been reported to include lactic acidosis in infants, which may be fatal, to chronic neurological dysfunction, brain malformations and intellectual disability. Some patients have a milder form characterized by recurrent episodes of ataxia and confusion, with no learning disabilities. These patients may survive into adulthood. Currently, it is not possible to predict the severity of disease from the patients genotype.