Infantile Refsum disease is one of three peroxisome biogenesis disorders which belong to the Zellweger spectrum of peroxisome biogenesis disorders (PBD-ZSD). The other two disorders are Zellweger syndrome (ZS) and neonatal adrenoleukodystrophy (NALD). Although they share a similar molecular basis for disease, Infantile Refsum disease is less severe than Zellweger syndrome.

Infantile Refsum disease is a developmental brain disorder. In addition, patients can show a reduction in central nervous system (CNS) myelin (particularly cerebral), which is referred to as (hypomyelination). Myelin is critical for normal CNS functions. Patients can also show postdevelopmental sensorineuronal degeneration that leads to a progressive loss of hearing and vision.

Infantile Refsum disease can also affect the function of many other organ systems. Patients can show craniofacial abnormalities, hepatomegaly (enlarged liver), and progressive adrenal dysfunction. Newborns may present with profound hypotonia (low muscle tone), and a poor ability to feed. In some patients, a progressive leukodystrophy has been observed that has a variable age of onset.

Zellweger syndrome is one of three peroxisome biogenesis disorders which belong to the Zellweger spectrum of peroxisome biogenesis disorders (PBD-ZSD). The other two disorders are neonatal adrenoleukodystrophy (NALD), and infantile Refsum disease (IRD). Although all have a similar molecular basis for disease, Zellweger syndrome is the most severe of these three disorders.

Zellweger syndrome is associated with impaired neuronal migration, neuronal positioning, and brain development. In addition, individuals with Zellweger syndrome can show a reduction in central nervous system (CNS) myelin (particularly cerebral), which is referred to as hypomyelination. Myelin is critical for normal CNS functions, and in this regard, serves to insulate nerve fibers in the brain. Patients can also show postdevelopmental sensorineuronal degeneration that leads to a progressive loss of hearing and vision.

Zellweger syndrome can also affect the function of many other organ systems. Patients can show craniofacial abnormalities (such as a high forehead, hypoplastic supraorbital ridges, epicanthal folds, midface hypoplasia, and a large fontanel), hepatomegaly (enlarged liver), chondrodysplasia punctata (punctate calcification of the cartilage in specific regions of the body), eye abnormalities, and renal cysts. Newborns may present with profound hypotonia (low muscle tone), seizures, apnea, and an inability to eat.

Individuals with Refsum disease present with neurologic damage, cerebellar degeneration, and peripheral neuropathy. Onset is most commonly in childhood/adolescence with a progressive course, although periods of stagnation or remission occur. Symptoms also include ataxia, scaly skin (ichthyosis), difficulty hearing, and eye problems including retinitis pigmentosa, cataracts, and night blindness. In 80% of patients diagnosed with Refsum disease, sensorineural hearing loss has been reported. This is hearing loss as the result of damage to the inner ear or the nerve connected to ear to the brain.

Infantile Refsum disease (IRD), also called infantile phytanic acid storage disease, is a rare autosomal recessive congenital peroxisomal biogenesis disorder within the Zellweger spectrum. These are disorders of the peroxisomes that are clinically similar to Zellweger syndrome and associated with mutations in the "PEX" family of genes. IRD is associated with deficient phytanic acid catabolism, as is Adult Refsum disease, but they are different disorders that should not be confused.

Like many other genetic disorders that affect lipid metabolism, there are several forms of MLD, which are late infantile, juvenile, and adult.

- In the "late infantile form", which is the most common form of MLD (50–60%), affected children begin having difficulty walking after the first year of life, usually at 15–24 months. Symptoms include muscle wasting and weakness, muscle rigidity, developmental delays, progressive loss of vision leading to blindness, convulsions, impaired swallowing, paralysis, and dementia. Children may become comatose. Untreated, most children with this form of MLD die by age 5, often much sooner.

- Children with the "juvenile form" of MLD (onset between 3 and 10 years of age) usually begin with impaired school performance, mental deterioration, and dementia and then develop symptoms similar to the late infantile form but with slower progression. Age of death is variable, but normally within 10 to 15 years of symptom onset although some juveniles can live for several decades or longer after onset.

- The "adult form" commonly begins after age 16 often with an onset in the 4th or 5th decade of life and presents as a psychiatric disorder or progressive dementia. Adult-onset MLD usually progresses more slowly than the late infantile and juvenile forms, with a protracted course of a decade or more.

Palliative care can help with many of the symptoms and usually improves quality of life and longevity.

Carriers have low enzyme levels compared to their family population ("normal" levels vary from family to family) but even low enzyme levels are adequate to process the body's sulfatide.

Most patients with ML IV show psychomotor retardation (i.e., delayed development of movement and coordination), corneal opacity, retinal degeneration and other ophthalmological abnormalities. Other symptoms include agenesis of the corpus callosum, iron deficiency resulting from an absence of acid secretion in the stomach, achlorhydria. Achlorhydria in these patients results in an increase in blood gastrin levels. These symptoms typically manifest early in life (within the first year). After disease onset there occurs a period of stability, typically lasting two to three decades during which very little disease progression occurs.

Tay–Sachs disease is typically first noticed in infants around 6 months old displaying an abnormally strong response to sudden noises or other stimulus, known as the "startle response," because they are startled. There may also be listlessness or muscle stiffness (hypertonia). The disease is classified into several forms, which are differentiated based on the onset age of neurological symptoms.

- Infantile Tay–Sachs disease. Infants with Tay–Sachs disease appear to develop normally for the first six months after birth. Then, as neurons become distended with gangliosides, a relentless deterioration of mental and physical abilities begins. The child may become blind, deaf, unable to swallow, atrophied, and paralytic. Death usually occurs before the age of four.

- Juvenile Tay–Sachs disease. Juvenile Tay–Sachs disease is rarer than other forms of Tay–Sachs, and usually is initially seen in children between two and ten years old. People with Tay–Sachs disease develop cognitive and motor skill deterioration, dysarthria, dysphagia, ataxia, and spasticity. Death usually occurs between the age of five to fifteen years.

- Adult/Late-Onset Tay–Sachs disease. A rare form of this disease, known as Adult-Onset or Late-Onset Tay–Sachs disease, usually has its first symptoms during the 30s or 40s. In contrast to the other forms, late-onset Tay–Sachs disease is usually not fatal as the effects can stop progressing. It is frequently misdiagnosed. It is characterized by unsteadiness of gait and progressive neurological deterioration. Symptoms of late-onset Tay–Sachs – which typically begin to be seen in adolescence or early adulthood – include speech and swallowing difficulties, unsteadiness of gait, spasticity, cognitive decline, and psychiatric illness, particularly a schizophrenia-like psychosis. People with late-onset Tay–Sachs may become full-time wheelchair users in adulthood.

Until the 1970s and 1980s, when the disease's molecular genetics became known, the juvenile and adult forms of the disease were not always recognized as variants of Tay–Sachs disease. Post-infantile Tay–Sachs was often misdiagnosed as another neurological disorder, such as Friedreich's ataxia.

Onset of late infantile GM1 is typically between ages 1 and 3 years.

Neurological symptoms include ataxia, seizures, dementia, and difficulties with speech.

Symptoms of early infantile GM1 (the most severe subtype, with onset shortly after birth) may include neurodegeneration, seizures, liver enlargement (hepatomegaly), spleen enlargement (splenomegaly), coarsening of facial features, skeletal irregularities, joint stiffness, distended abdomen, muscle weakness, exaggerated startle response to sound, and problems with gait.

About half of affected patients develop cherry-red spots in the eye.

Children may be deaf and blind by age 1 and often die by age 3 from cardiac complications or pneumonia.

- Autosomal recessive disorder; beta-galactosidase deficiency; neuronal storage of GM1 ganglioside and visceral storage of galactosyl oligosaccharides and keratan sulfate.

- Early psychomotor deterioration: decreased activity and lethargy in the first weeks; never sit; feeding problems - failure to thrive; visual failure (nystagmus noted) by 6 months; initial hypotonia; later spasticity with pyramidal signs; secondary microcephaly develops; decerebrate rigidity by 1 year and death by age 1–2 years (due to pneumonia and respiratory failure); some have hyperacusis.

- Macular cherry-red spots in 50% by 6–10 months; corneal opacities in some

- Facial dysmorphology: frontal bossing, wide nasal bridge, facial edema (puffy eyelids); peripheral edema, epicanthus, long upper lip, microretrognathia, gingival hypertrophy (thick alveolar ridges), macroglossia

- Hepatomegaly by 6 months and splenomegaly later; some have cardiac failure

- Skeletal deformities: flexion contractures noted by 3 months; early subperiosteal bone formation (may be present at birth); diaphyseal widening later; demineralization; thoracolumbar vertebral hypoplasia and beaking at age 3–6 months; kyphoscoliosis. *Dysostosis multiplex (as in the mucopolysaccharidoses)

- 10–80% of peripheral lymphocytes are vacuolated; foamy histiocytes in bone marrow; visceral mucopolysaccharide storage similar to that in Hurler disease; GM1 storage in cerebral gray matter is 10-fold elevated (20–50-fold increased in viscera)

- Galactose-containing oligosacchariduria and moderate keratan sulfaturia

- Morquio disease Type B: Mutations with higher residual beta-galactosidase activity for the GM1 substrate than for keratan sulfate and other galactose-containing oligosaccharides have minimal neurologic involvement but severe dysostosis resembling Morquio disease type A (Mucopolysaccharidosis type 4).

Refsum disease, also known as classic or adult Refsum disease, heredopathia atactica polyneuritiformis, phytanic acid oxidase deficiency and phytanic acid storage disease, is an autosomal recessive neurological disease that results from the over-accumulation of phytanic acid in cells and tissues. It is one of several disorders named after Norwegian neurologist Sigvald Bernhard Refsum (1907–1991). Refsum disease typically is adolescent onset and is diagnosed by above average levels of phytanic acid. Humans obtain the necessary phytanic acid primarily through diet. It is still unclear what function phytanic acid plays physiologically in humans, but has been found to regulate fatty acid metabolism in the liver of mice.

The symptoms of LSD vary, depending on the particular disorder and other variables such as the age of onset, and can be mild to severe. They can include developmental delay, movement disorders, seizures, dementia, deafness, and/or blindness. Some people with LSDhave enlarged livers (hepatomegaly) and enlarged spleens (splenomegaly), pulmonary and cardiac problems, and bones that grow abnormally.

Sandhoff disease symptoms are clinically indeterminable from Tay–Sachs disease. The classic infantile form of the disease has the most severe symptoms and is incredibly hard to diagnose at this early age. The first signs of symptoms begin before 6 months of age and the parents’ notice when the child begins regressing in their development. If the children had the ability to sit up by themselves or crawl they will lose this ability. This is caused by a slow deterioration of the muscles in the child’s body from the buildup of GM2 gangliosides. Since the body is unable to create the enzymes it needs within the central nervous system it is unable to attach to these gangliosides to break them apart and make them non-toxic. With this buildup there are several symptoms that begin to appear such as muscle/motor weakness, sharp reaction to loud noises, blindness, deafness, inability to react to stimulants, respiratory problems and infections, mental retardation, seizures, cherry red spots in the retina, enlarged liver and spleen (hepatosplenomegaly), pneumonia, or bronchopneumonia.

The other two forms of Sandhoff disease have similar symptoms but to a lesser extent. Adult and juvenile forms of Sandhoff disease are more rare than the infantile form. In these cases victims suffer cognitive impairment (retardation) and a loss of muscle coordination that impairs and eventually destroys their ability to walk; the characteristic red spots in the retina also develop. The adult form of the disease, however, is sometimes milder, and may only lead to muscle weakness that impairs walking or the ability to get out of bed.

Males show more serious symptoms than females affected by this disorder.

The symptoms for males are:

1. Profound sensorineural hearing loss i.e, a complete or almost complete loss of hearing caused by abnormalities in the inner ear.

2. Weak muscle tone - Hypotonia.

3. Impaired muscle coordination - Ataxia.

4. Developmental delay.

5. Intellecual disability.

6. Vision loss caused by optic nerve atrophy in early childhood.

7. Peripheral neuropathy.

8. Recurrent infections, especially in the respiratory system.

9. Muscle weakness caused by recurrent infections.

Symptoms for females:

Very rarely seen hearing loss that begins in adulthood (age > 20 years) combined with ataxia and neuropathy. Optic atrophy and retinitis pigmentosa observed in some cases too.

There are three main types of the disease each with its own distinctive symptoms.

Type I infantile form, infants will develop normally until about a year old. At this time, the affected infant will begin to lose previously acquired skills involving the coordination of physical and mental behaviors. Additional neurological and neuromuscular symptoms such as diminished muscle tone, weakness, involuntary rapid eye movements, vision loss, and seizures may become present. With time, the symptoms worsen and children affected with this disorder will experience a decreased ability to move certain muscles due to muscle rigidity. The ability to respond to external stimuli will also decrease. Other symptoms include neuroaxonal dystrophy from birth, discoloration of skin, Telangiectasia or widening of blood vessels.

Type II adult form, symptoms are milder and may not appear until the individual is in his or her 30s. Angiokeratomas, an increased coarsening of facial features, and mild intellectual impairment are likely symptoms.

Type III is considered an intermediate disorder. Symptoms vary and can include to be more severe with seizures and mental retardation, or less severe with delayed speech, a mild autistic like presentation, and/or behavioral problems.

The infantile form usually comes to medical attention within the first few months of life. The usual presenting features are cardiomegaly (92%), hypotonia (88%), cardiomyopathy (88%), respiratory distress (78%), muscle weakness (63%), feeding difficulties (57%) and failure to thrive (50%).

The main clinical findings include floppy baby appearance, delayed motor milestones and feeding difficulties. Moderate hepatomegaly may be present. Facial features include macroglossia, wide open mouth, wide open eyes, nasal flaring (due to respiratory distress), and poor facial muscle tone. Cardiopulmonary involvement is manifested by increased respiratory rate, use of accessory muscles for respiration, recurrent chest infections, decreased air entry in the left lower zone (due to cardiomegaly), arrhythmias and evidence of heart failure.

Median age at death in untreated cases is 8.7 months and is usually due to cardiorespiratory failure.

This exclusively myopathic form is the most prevalent and least severe phenotypic presentation of this disorder. Characteristic signs and symptoms include rhabdomyolysis (breakdown of muscle fibers and subsequent release of myoglobin), myoglobinuria, recurrent muscle pain, and weakness. It is important to note that muscle weakness and pain typically resolves within hours to days, and patients appear clinically normal in the intervening periods between attacks. Symptoms are most often exercise-induced, but fasting, a high-fat diet, exposure to cold temperature, or infection (especially febrile illness) can also provoke this metabolic myopathy. In a minority of cases, disease severity can be exacerbated by three life-threatening complications resulting from persistent rhabdomyolysis: acute kidney failure, respiratory insufficiency, and episodic abnormal heart rhythms. Severe forms may have continual pain from general life activity. The adult form has a variable age of onset. The first appearance of symptoms usually occurs between 6 and 20 years of age but has been documented in patients as young as 8 months as well as in adults over the age of 50. Roughly 80% cases reported to date have been male.

Infants with Krabbe disease are normal at birth. Symptoms begin between the ages of 3 and 6 months with irritability, fevers, limb stiffness, seizures, feeding difficulties, vomiting, and slowing of mental and motor development. In the first stages of the disease, doctors often mistake the symptoms for those of cerebral palsy. Other symptoms include muscle weakness, spasticity, deafness, optic atrophy, optic nerve enlargement, blindness, paralysis, and difficulty when swallowing. Prolonged weight loss may also occur. Juvenile- and adult-onset cases of Krabbe disease also occur, which have similar symptoms but slower progression.

There are three main types of carnitine palmitoyltransferase II deficiency classified on the basis of tissue-specific symptomotology and age of onset:

- Mild to severe adult myopathic form

- Severe infantile multisystemic form

- Lethal neonatal form

It should be noted that among the few people diagnosed with CPT2, some have unknown and/or novel mutations that place them outside these three categories while remaining positive for CPT2.

This form differs from the infantile principally in the relative lack of cardiac involvement. The onset is more insidious and has a slower progression. Cardiac involvement may occur but is milder than in the infantile form. Skeletal involvement is more prominent with a predilection for the lower limbs.

Late onset features include impaired cough, recurrent chest infections, hypotonia, progressive muscle weakness, delayed motor milestones, difficulty swallowing or chewing and reduced vital capacity.

Prognosis depends on the age of onset on symptoms with a better prognosis being associated with later onset disease.

Phosphofructokinase deficiency also presents in a rare infantile form. Infants with this deficiency often display floppy infant syndrome (hypotonia), arthrogryposis, encephalopathy and cardiomyopathy. The disorder can also manifest itself in the central nervous system, usually in the form of seizures. PFK deficient infants also often have some type of respiratory issue. Survival rate for the infantile form of PFK deficiency is low, and the cause of death is often due to respiratory failure.

Late-onset PFK deficiency, as the name suggests, is a form of the disease that presents later in life. Common symptoms associated with late-onset phosphofructokinase deficiency are myopathy, weakness and fatigue. Many of the more severe symptoms found in the classic type of this disease are absent in the late-onset form.

Mucolipidosis type IV (ML IV or ML4) is an autosomal recessive lysosomal storage disorder. Individuals with the disorder have many symptoms including delayed psychomotor development and various ocular aberrations. The disorder is caused by mutations in the MCOLN1 gene, which encodes a non-selective cation channel, mucolipin1. These mutations disrupt cellular functions and lead to a neurodevelopmental disorder through an unknown mechanism. Researchers dispute the physiological role of the protein product and which ion it transports.

A lipid storage disorder (or lipidosis) can be any one of a group of inherited metabolic disorders in which harmful amounts of fats or lipids accumulate in some of the body’s cells and tissues. People with these disorders either do not produce enough of one of the enzymes needed to metabolize and break down lipids or they produce enzymes that do not work properly. Over time, this excessive storage of fats can cause permanent cellular and tissue damage, particularly in the brain, peripheral nervous system, liver, spleen and bone marrow.

Inside cells under normal conditions, lysosomes convert, or metabolize, lipids and proteins into smaller components to provide energy for the body.

Peroxisomal disorders represent a class of medical conditions caused by defects in peroxisome functions. This may be due to defects in single enzymes important for peroxisome function or in peroxins, proteins encoded by "PEX" genes that are critical for normal peroxisome assembly and biogenesis.

Symptoms are related to the organs in which sphingomyelin accumulates. Enlargement of the liver and spleen (hepatosplenomegaly) may cause reduced appetite, abdominal distension, and pain. Enlargement of the spleen (splenomegaly) may also cause low levels of platelets in the blood (thrombocytopenia).

Accumulation of sphingomyelin in the central nervous system (including the cerebellum) results in unsteady gait (ataxia), slurring of speech (dysarthria), and difficulty in swallowing (dysphagia). Basal ganglia dysfunction causes abnormal posturing of the limbs, trunk, and face (dystonia). Upper brainstem disease results in impaired voluntary rapid eye movements (supranuclear gaze palsy). More widespread disease involving the cerebral cortex and subcortical structures causes gradual loss of intellectual abilities, causing dementia and seizures.

Bones also may be affected: symptoms may include enlarged bone marrow cavities, thinned cortical bone, or a distortion of the hip bone called coxa vara. Sleep-related disorders, such as sleep inversion, sleepiness during the day and wakefulness at night, may occur. Gelastic cataplexy, the sudden loss of muscle tone when the affected patient laughs, is also seen.