Glycerol Kinase Deficiency causes the condition known as hyperglycerolemia, an accumulation of glycerol in the blood and urine. This excess of glycerol in bodily fluids can lead to many more potentially dangerous symptoms. Common symptoms include vomiting and lethargy. These tend to be the only symptoms, if any, present in adult GKD which has been found to present with fewer symptoms than infant or juvenile GKD. When GKD is accompanied by Duchenne Muscular Dystrophy and Adrenal Hypoplasia Congenita, also caused by mutations on the Xp21 chromosome, the symptoms can become much more severe. Symptoms visible at or shortly after birth include:

- cryptorchidism

- strabismus

- seizures

Some other symptoms that become more noticeable with time would be:

- metabolic acidosis

- hypoglycemia

- adrenal cortex insufficiency

- learning disabilities

- osteoporosis

- myopathy

Many of the physically visible symptoms, such as cryptorchidism, strabismus, learning disabilities, and myopathy, tend to have an added psychological effect on the subject due to the fact that they can set him or her apart from those without GKD. Cryptorchidism, the failure of one or both of the testes to descend to the scrotum, has been known to lead to sexual identity confusion amongst young boys because it is such a major physiological anomaly. Strabismus is the misalignment of one’s eyes. Typically, one is focused but the other is “lazy” and is directed inward or out ward (up and down is less common but does occur).

The onset of this disease is usually noticed in childhood, but often not diagnosed until the third or fourth decade of life. Symptoms include exercise intolerance with muscle pain, early fatigue, painful cramps, and myoglobin in the urine (often provoked by a bout of exercise). Myoglobinuria may result from the breakdown of skeletal muscle known as rhabdomyolysis, a condition in which muscle cells breakdown, sending their contents into the bloodstream.

Patients may exhibit a “second wind” phenomenon. This is characterized by the patient’s better tolerance for aerobic exercise such as walking and cycling after approximately 10 minutes. This is attributed to the combination of increased blood flow and the ability of the body to find alternative sources of energy, like fatty acids and proteins. In the long term, patients may exhibit renal failure due to the myoglobinuria, and with age, patients may exhibit progressively increasing weakness and substantial muscle loss.

Patients may present at emergency rooms with severe fixed contractures of the muscles and often severe pain. These require urgent assessment for rhabdomyolysis as in about 30% of cases this leads to acute renal failure. Left untreated this can be life-threatening. In a small number of cases compartment syndrome has developed, requiring prompt surgical referral.

Classic phosphofructokinase deficiency is the most common type of this disorder. This type presents with exercise-induced muscle cramps and weakness (sometimes rhabdomyolysis), myoglobinuria, as well as with haemolytic anaemia causing dark urine a few hours later.

Hyperuricemia is common, due to the kidneys' inability to process uric acid following damage resulting from processing myoglobin. Nausea and vomiting following strenuous exercise is another common indicator of classic PFK deficiency. Many patients will also display high levels of bilirubin, which can lead to a jaundiced appearance. Symptoms for this type of PFK deficiency usually appear in early childhood.

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.

Patients generally have a benign course, and typically present with hepatomegaly and growth retardation early in childhood. Mild hypoglycemia, hyperlipidemia, and hyperketosis may occur. Lactic acid and uric acid levels may be normal. However, lactic acidosis may occur during fasting.

The low incidence of this syndrome is often related to aldolase A's essential glycolytic role along with its exclusive expression in blood and skeletal muscle. Early developmental reliance and constitutive function prevents severe mutation in successful embryos. Infrequent documentation thus prevents clear generalisation of symptoms and causes. However five cases have been well described. ALDOA deficiency is diagnosed through reduced aldoA enzymatic activity, however, both physiological response and fundamental causes vary.

The symptoms of SSADH deficiency fall into three primary categories: neurological, psychiatric, and ocular. The most constant features seen are developmental delay, hypotonia and intellectual disability. Nearly half of patients seen manifest ataxia, behavior problems, seizures, and hyporeflexia.

The age of onset ranges from newborn period to 25 years. Problems unique to neonates can include prematurity, lethargy, decreased sucking, respiratory difficulty and hypoglycemia. Gastrointestinal symptoms have been seen primarily in this

population and are usually related to increased feeding.

Ocular problems related to the disorder include strabismus, nystagmus, retinitis, disc pallor, and oculomotor apraxia.

Over half of the patients with SSADH deficiency have seizures. These include absence, tonic clonic, and convulsive status epilepticus. It is unclear whether decreased levels of GABA or elevated levels of GHB are responsible for these seizures but alterations in these neurotransmitters and their receptor binding or neurotransmitter transport is hypothesized to play a role in the pathogenesis of the seizures in this population.

Symptoms associated with SSADH may be mild, moderate or severe and often vary greatly from case to case. The symptoms of SSADH are caused by the accumulation of GHB in the brain and include the following manifestations (Defined as: common, > 70% of patients; frequent 30-70% of patients;unusual, < 30% of patients):

Common manifestations include:

- Delayed gross motor development

- Delayed mental development

- Delayed fine motor skill development

- Delayed speech and language development

- Hypotonia

Frequent manifestations include:

- Seizures

- Hyporeflexia

- Ataxia

- Behavioral problems

- Hyperkinesis

Unusual manifestations include:

- Neonatal problems

- EEG abnormalities

- Psychoses

- MRI or X-ray computed tomography abnormalities

- Oculomotor apraxia

- Microcephaly

- Macrocephaly

- Hyperreflexia

- Somnolence

- Choreoathetosis

- Myopathy

Glycogen storage disease type V (GSD-V) is a metabolic disorder, more specifically a glycogen storage disease, caused by a deficiency of myophosphorylase. Its incidence is reported as 1 in 100,000, approximately the same as glycogen storage disease type I.

The disease was first reported in 1951 by Dr. Brian McArdle of Guy's Hospital, London.

Glycerol Kinase Deficiency (GKD) is an X-linked recessive enzyme defect that is heterozygous in nature. Three clinically distinct forms of this deficiency have been proposed, namely infantile, juvenile, and adult. National Institutes of Health and its Office of Rare Diseases Research (ORDR) branch classifies GKD as a rare disease, known to affect fewer than 200,000 individuals in the United States. The responsible gene lies in a region containing genes in which deletions can cause Duchenne muscular dystrophy and adrenal hypoplasia congenita. Combinations of these three genetic defects including GKD are addressed medically as Complex GKD.

Hyperglycerolemia, also known as Glycerol kinase deficiency (GKD), is a genetic disorder where the enzyme glycerol kinase is deficient resulting in a build-up of glycerol in the body. Glycerol kinase is responsible for synthesizing triglycerides and glycerophospholipids in the body. Excess amounts of glycerol can be found in the blood and/ or urine. Hyperglycerolmia occurs more frequently in males. Hyperglycerolemia is listed as a “rare disease” by the Office of Rare Diseases (ORD) of the National Institutes of Health (NIH), which means it affects less than 200,000 people in the US population (U.S. Department of Health & Human Services), or less than about 1 in 1500 people.

Aldolase A deficiency, also called ALDOA deficiency, red cell aldolase deficiency or glycogen storage disease type 12 (GSD XII) is an autosomal recessive metabolic disorder resulting in a deficiency of the enzyme aldolase A; the enzyme is found predominantly in red blood cells and muscle tissue. The deficiency may lead to hemolytic anaemia as well as myopathy associated with exercise intolerance and rhabdomyolysis in some cases.

D-Glyceric Acidemia should not be confused with L-Glyceric Acidemia (a.k.a. L-glyceric aciduria, a.k.a. primary hyperoxaluria type II ), which is associated with mutations in the "GRHPR" (encoding for the enzyme 'glyoxylate reductase/hydroxypyruvate reductase').

Mevalonate kinase deficiency, also called mevalonic aciduria and hyper immunoglobin D syndrome is an autosomal recessive metabolic disorder that disrupts the biosynthesis of cholesterol and isoprenoids.

It is characterized by an elevated level of immunoglobin D in the blood.

The enzyme is involved in biosynthesis of cholesterols and isoprenoids. The enzyme is necessary for the conversion of mevalonate to mevalonate-5-phosphate in the presence of Mg2+ [Harper’s biochemistry manual]. Mevalonate kinase deficiency causes the accumulation of mevalonate in urine and hence the activity of the enzyme is again reduced Mevalonate kinase deficiency. It was first described as HIDS in 1984.

Glycogen storage disease type VI (GSD VI) is a type of glycogen storage disease caused by a deficiency in liver glycogen phosphorylase or other components of the associated phosphorylase cascade system. It is also known as "Hers' disease", after Henri G. Hers, who characterized it in 1959. The scope of GSD VI now also includes glycogen storage disease type VIII, IX (caused by phosphorylase b kinase deficiency) and X (deficiency protein kinase A).

The incidence of GSD VI is approximately 1 case per 65,000–85,000 births, representing approximately 30% all cases of glycogen storage disease. Approximately 75% of these GSD VI cases result from the X-linked recessive forms of phosphorylase kinase deficiency, all other forms are autosomal recessive.

Dolichol kinase deficiency is a cutaneous condition caused by a mutation in the dolichol kinase gene.

It is also known as Congenital disorder of glycosylation 1m.

Succinic semialdehyde dehydrogenase deficiency (SSADHD), also known as 4-hydroxybutyric aciduria or gamma-hydroxybutyric aciduria, is a rare autosomal recessive disorder of the degradation pathway of the inhibitory neurotransmitter γ-aminobutyric acid, or GABA. The disorder has been identified in approximately 350 families, with a significant proportion being consanguineous families. The first case was identified in 1981 and published in a Dutch clinical chemistry journal that highlighted a person with a number of neurological conditions such as delayed intellectual, motor, speech, and language as the most common manifestations. Later cases reported in the early 1990s began to show that hypotonia, hyporeflexia, seizures, and a nonprogressive ataxia were frequent clinical features as well.

SSADH deficiency is caused by an enzyme deficiency in GABA degradation. Under normal conditions, SSADH works with the enzyme GABA transaminase to convert GABA to succinic acid. Succinic acid can then be utilized for energy production via the Krebs cycle. However, because of the deficiency, the final intermediate of the GABA degradation pathway, succinic semialdehyde, accumulates and cannot be oxidized to succinic acid and is therefore reduced to gamma-hydroxybutyric acid (GHB) by gamma-hydroxybutyric dehydrogenase. This causes elevations in GHB and is believed to be the trademark of this disorder and cause for the neurological manifestations seen.

Glycerate kinase is an enzyme that catalyzes the conversion of D-glyceric acid (a.k.a. D-glycerate) to 2-phosphoglycerate. This conversion is an intermediary reaction found in several metabolic pathways, including the degradation (break-down; catabolism) of serine, as well as the breakdown of fructose.

A deficiency in glycerate kinase activity leads to the accumulation of D-glyceric acid (a.k.a. D-glycerate) in bodily fluids and tissues. D-glyceric acid can be measured in a laboratory that performs "analyte testing" for "organic acids" in blood (plasma) and urine.

Symptoms of the disease (in its most severe form) include progressive neurological impairment, mental/motor retardation, hypotonia, seizures, failure to thrive and metabolic acidosis.

Glycerol and glycerol kinase activity analyses are usually not offered by routine general medical laboratories. To diagnose hyperglycerolemia, blood and urine can be tested for the amounts of glycerol present.

There are three clinical forms of GKD: infantile, juvenile, and adult. The infantile form is associated with severe developmental delay and results in a syndrome with Xp21 gene deletion with congenital adrenal hypoplasia and/or Duchenne muscular dystrophy. The infantile diagnosis is made by measuring plasma glycerol and is characterized by glycerol levels between 1.8 and 8.0 mmol/L and glyceroluria more than 360 mmol/24h. To confirm the diagnosis, genetic testing of the Xp21 gene is definitive. Children with GKD have severe hypoglycemic episodes and profound metabolic acidosis, or are completely symptom free. Individuals who are unable to form glucose from the glycerol released during triglyceride catabolism also the hypoglycemic episodes often disappear during adolescence. Patients with the juvenile and adult forms often have no symptoms and are diagnosed fortuitously when a medical professional tests for another medical condition. The juvenile form is an uncommon form characterized by Reye syndrome-like clinical manifestations including episodic vomiting, acidemia, and disorders of consciousness.

The signs and symptoms in glycogen storage disease type IX include:

- Enlarged liver

- Slowed growth

- Motor development delay (mild)

- Low blood sugar accompanied by ketosis

- Lack of muscle tone

Most of these signs and symptoms diminish as adulthood sets in.

Wolcott–Rallison syndrome, WRS, is a rare, autosomal recessive disorder with infancy-onset diabetes mellitus, multiple epiphyseal dysplasia, osteopenia, mental retardation or developmental delay, and hepatic and renal dysfunction as main clinical findings. Patients with WRS have mutations in the EIF2AK3 gene, which encodes the pancreatic eukaryotic translation initiation factor 2-alpha kinase 3.

Mevalonate kinase deficiency causes an accumulation of mevalonic acid in the urine, resulting from insufficient activity of the enzyme mevalonate kinase (ATP:mevalonate 5-phosphotransferase; EC 2.7.1.36).

The disorder was first described in 1985.

Classified as an inborn error of metabolism, mevalonate kinase deficiency usually results in developmental delay, hypotonia, anemia, hepatosplenomegaly, various dysmorphic features, mental retardation, an overall failure to thrive and several other features.

Symptoms can be extremely varied among those suffering from pyruvate kinase deficiency. The majority of those suffering from the disease are detected at birth while some only present symptoms during times of great physiological stress such as pregnancy, or with acute illnesses (viral disorders). Symptoms are limited to or most severe during childhood. Among the symptoms of pyruvate kinase deficiency are:

- Mild to severe hemolytic Anemia

- Cholecystolithiasis

- Tachycardia

- Hemochromatosis

- Icteric sclera

- Splenomegaly

- Leg ulcers

- Jaundice

- Fatigue

- Shortness of breath

Initially, patients with neonatal or early-childhood onset diabetes are possible candidates for having Wolcott–Rallison syndrome. The other symptoms include the multiple epiphyseal dysplasia, osteopenia, intellectual disability, and hepatic and renal dysfunction. Patients with the symptoms that line up with Wolcott–Rallison syndrome can be suggested for genetics testing. The key way to test for this disease specifically is through genetic testing for the EIKF2AK3 mutation. Molecular genetic analysis can be done for the patient and the parents to test for de novo mutations or inherited. It can also show whether the patient's parents are heterozygotes or homozygotes for the normal phenotype. X-Rays can show bone age in relation to actual age. Typically the bond age is a few years less than the actual in the patients with WRS. Hypothyroidism is rare is WRS patients but can occur.

Horses with Type 1 PSSM usually appear normal at rest, but show signs of exertional rhabdomyolysis ("tying up") such as shortened stride, stiffness, firm musculature, sweating, pain or reluctance to exercise, when asked to perform light work. While episodes of exertional rhabdomyolysis is one of the most frequent signs associated with affected horses (reported in ~37% of affected animals), other common signs include gait abnormalities, shifting lameness, muscle weakness that may result in an inability to rise, colic-like pain, and muscle fasciculation, atrophy, and/or stiffness (most commonly seen in the semimembranosis, semitendinosis, and longissimus muscles).

These clinical signs usually first become apparent when the horse is placed into training as a young animal; however, affected horses will show histological changes consistent with muscle damage at one month of age, and may also show elevations in creatine kinase (CK), an enzyme that elevates with muscle damage. Concurrent illness, such as respiratory or gastrointestinal infection, can lead to elevations in CK and potentially life-threatening rhabdomyolysis, even without exercise. Horses with PSSM often have a persistently elevated CK at rest, which differentiates the disease from recurrent exertional rhabdomyolysis, in which horses have normal CK concentrations between episodes.

2,4 Dienoyl-CoA reductase deficiency is an inborn error of metabolism resulting in defective fatty acid oxidation caused by a deficiency of the enzyme 2,4 Dienoyl-CoA reductase. Lysine degradation is also affected in this disorder leading to hyperlysinemia. The disorder is inherited in an autosomal recessive manner, meaning an individual must inherit mutations in "NADK2," located at 5p13.2 from both of their parents. NADK2 encodes the mitochondrial NAD kinase. A defect in this enzyme leads to deficient mitochondrial nicotinamide adenine dinucleotide phosphate levels. 2,4 Dienoyl-CoA reductase, but also lysine degradation are performed by NADP-dependent oxidoreductases explaining how NADK2 deficiency can lead to multiple enzyme defects.

2,4-Dienoyl-CoA reductase deficiency was initially described in 1990 based on a single case of a black female who presented with persistent hypotonia. Laboratory investigations revealed elevated lysine, low levels of carnitine and an abnormal acylcarnitine profile in urine and blood. The abnormal acylcarnitine species was eventually identified as 2-trans,4-cis-decadienoylcarnitine, an intermediate of linoleic acid metabolism. The index case died of respiratory failure at four months of age. Postmortem enzyme analysis on liver and muscle samples revealed decreased 2,4-dienoyl-CoA reductase activity when compared to normal controls. A second case with failure to thrive, developmental delay, lactic acidosis and severe encephalopathy was reported in 2014.

2,4-Dienoyl-CoA reductase deficiency was included as a secondary condition in the American College of Medical Genetics Recommended Uniform Panel for newborn screening. Its status as a secondary condition means there was not enough evidence of benefit to include it as a primary target, but it may be detected during the screening process or as part of a differential diagnosis when detecting conditions included as primary target. Despite its inclusion in newborn screening programs in several states for a number of years, no cases have been identified via neonatal screening.