The signs and symptoms that may be present when an individual has hyperpipecolatemia may vary widely in both nature and severity, depending on the underlying disorder the affected individual has. Hyperpipecolatemia is often present in individuals with peroxisomal biogenesis disorders (PBDs), specifically those considered Zellweger spectrum disorders
. These are a group of conditions that have overlapping signs and symptoms and affect many parts of the body. This group of disorders includes Zellweger syndrome
, neonatal adrenoleukodystrophy
(NALD), and infantile Refsum disease
; some experts believe that hyperpipecolatemia also falls into this category as its own entity.
These conditions were once thought to be distinct disorders but are now considered by some to be part of the same disease spectrum. Zellweger syndrome is the most severe form of the Zellweger spectrum, NALD is intermediate in severity, and infantile Refsum disease is the least severe form.
Those that consider hyperpipecolatemia to be part this spectrum consider it to be a relatively milder disease.
In some cases, it can be difficult to distinguish between the three conditions that make up the Zellweger spectrum.
Individuals with Zellweger syndrome develop signs and symptoms of the condition during the newborn period. These infants experience weak muscle tone (hypotonia), feeding problems, hearing loss, vision loss, and seizures. Children with Zellweger syndrome also develop life-threatening problems in other organs and tissues, such as the liver, heart, and kidneys. They may have skeletal abnormalities, including a large space between the bones of the skull (fontanels) and characteristic bone spots known as chondrodysplasia punctata that can be seen with an X-ray. Affected individuals have distinctive facial features, including a flattened face, broad nasal bridge, and high forehead. Children with Zellweger syndrome typically do not survive beyond the first year of life.
People with NALD or infantile Refsum disease have more variable features than those with Zellweger syndrome and usually do not develop signs and symptoms of the disease until late infancy or early childhood. They may have many of the features seen in more severely affected individuals; however, their condition typically progresses more slowly. Children with these less severe conditions often have hypotonia, vision problems, hearing loss, liver dysfunction, some degree of developmental delay, and some degree of intellectual disability. Most people with NALD survive into childhood, and those with infantile Refsum disease may reach adulthood. In rare cases, individuals at the mildest end of the Zellweger spectrum have developmental delay in childhood and hearing loss or vision problems beginning in adulthood.Pyridoxine-dependent epilepsy
, another condition in which hyperpipecolatemia may be present, is a condition that involves seizures beginning in infancy or, in some cases, before birth. Those affected typically experience prolonged seizures lasting several minutes (status epilepticus). These seizures involve muscle rigidity, convulsions, and loss of consciousness (tonic-clonic seizures). Additional features of pyridoxine-dependent epilepsy include low body temperature (hypothermia), poor muscle tone (dystonia) soon after birth, and irritability before a seizure episode. In rare instances, children with this condition do not have seizures until they are 1 to 3 years old. Anticonvulsant drugs, which are usually given to control seizures, are ineffective in people with pyridoxine-dependent epilepsy. Instead, people with this type of seizure are medically treated with large daily doses of pyridoxine (a type of vitamin B6 found in food). If left untreated, people with this condition can develop severe brain dysfunction (encephalopathy). Even though seizures can be controlled with pyridoxine, neurological problems such as developmental delay and learning disorders may still occur.
A few cases have been reported of individuals with isolated hyperpipecolatemia combined with varying degrees of intellectual deficit, hypotonia, or Joubert's syndrome