Metabolic Disorders With Associated Movement Abnormalities

BH4 Defects with Hyperphenylalaninemia

Individuals in this group have defects which include those with autosomal recessively inherited forms of GTPCH-1 (GCH1) deficiency, 6-PTS deficiency, PCD deficiency, and DHPR deficiency. ^, Since each produces hyperphenylalaninemia and reduced synthesis of monoamines, clinical signs and symptoms tend to overlap.

Early presentation in the neonatal period, presumably due to hyperphenylalaninemia, includes hypotonia, poor suck, diminished movements, and microcephaly. Generally, starting several months later, additional monoaminergic symptoms appear including autonomic symptoms (hypersalivation, temperature instability, excessive diaphoresis, and blood pressure lability), oculogyric crises, swallowing difficulties, variable hypokinetic and hyperkinetic movements, seizures, and cognitive impairment. ^{, ,} These patients are often identified by neonatal screening for phenylketonuria (PKU). In DHPR deficiency, a secondary reduction in central nervous system (CNS) folate has led to perivascular basal ganglia calcification and multifocal subcortical perivascular demyelination. ^, Follow-up testing of urine pterins (biopterin and neopterin) and measurement of DHPR activity in blood are necessary to pinpoint the defect.

BH4 Defects Without Hyperphenylalaninemia

Tyrosine Hydroxylase Deficiency

TH, the rate-limiting enzyme in the biosynthesis of dopamine, catalyzes the conversion of l -tyrosine to l -dihydroxyphenylalanine. TH deficiency is an autosomal recessive disorder secondary to various point mutations mutations in the TH gene. ^, Presenting phenotypes range from severe onsets in infancy to milder juvenile DRD or juvenile parkinsonism, depending on residual enzyme activity. Symptoms in early onset cases include psychomotor retardation, rigidity, hypokinesia, axial hypotonia, and paroxysmal eye movements. In other presentations, cases have included parkinsonism, gait disorder with stiffness after exercise, dystonia, tremor, and ataxia.

Diagnosis is confirmed by genetic analysis and biochemical testing showing reduced CSF levels of dopamine, norepinephrine, HVA, and MHPG with normal 5-HIAA, biopterin, and neopterin levels. ^, The CSF HVA:5-HIAA ratio is < 1 (normal 1.0–3.7). Since TH is primarily expressed in the brain and adrenal gland, enzymatic assessment is generally not feasible. Treatment includes administration of conservative doses of levodopa/carbidopa to minimize l -dopa sensitivity and severe dyskinesias. In general, medication responses for motor symptoms and involuntary movements in individuals who tolerate l -dopa are good. Additional therapeutic recommendations include: the use of an MAO-B inhibitor (selegiline or rasagiline) to prevent breakdown of formed neurotransmitter; dopamine agonists (e.g., pramipexole, ropinirole, rotigotine); and a selective central M1 cholinergic receptor blocker (biperiden). ^, Deep brain stimulation was beneficial in a single case.

Amino Acid Decarboxylase (AADC)/Aromatic l -Amino Acid Decarboxylase (ALAAD) Deficiency

AADC/ALAAD, is a pyridoxal-5-phosphate-dependent enzyme that catalyzes both the formation of dopamine from l -dopa and serotonin from 5-hydroxytryptophan (5-HTP). Deficiency of this enzyme leads to a profound reduction of CSF serotonin and catecholamines. AADC deficiency is associated with mutations in the DDC gene. Although onset and phenotype can be variable, clinical symptoms usually begin in childhood. Major presenting problems include developmental delay, hypotonia, and oculogyric crises. ^, About 50% also present with movement disorders including arm and leg extension, dystonia, athetosis, myoclonus, torticollis, and bulbar dysfunction. Autonomic symptoms, associated with monoamine neurotransmitter deficiency, have included ptosis, miosis, sweating, temperature instability, hypotension, gastroesophageal reflux, and sleep disturbances. ^, Milder phenotypes have been reported in siblings with hypersomnolence, fatigability, and dystonia as well as in older individuals. ^{, ,} Magnetic resonance imaging (MRI) scans may have mild cortical atrophy and EEGs spike or polyspike bursts.

Classic laboratory diagnostic findings include marked CSF reductions of dopamine, HVA, serotonin, 5-HIAA, norepinephrine, and 3-MHPG. Levels of l -dopa and its metabolite, 3- O -methyldopa, are elevated since l -dopa cannot be decarboxylated to dopamine. The CSF pterin profile is normal. Plasma and fibroblast AADC are markedly reduced. A secondary deficiency of AADC, caused by a lack of pyridoxal 5-phosphate, has been reported.

Pharmacological treatments are variable and satisfactory in about 20% of patients. Therapy with monoamine oxidase (MAO) inhibitors and dopamine agonists has improved some symptoms but not signs of developmental delay. Although l -dopa would not be expected to be beneficial, several patients did experience improvement of symptoms, possibly due to a mutation that alters the binding affinity of the protein for l -dopa. High-dose pyridoxal phosphate is also recommended since B6 is a cofactor for AADC. Serotonergic agents have not been of benefit.

In contrast to pharmacotherapy, gene therapy provides a potentially promising new treatment for patients with AADC deficiency. Clinical studies in children and adolescents receiving adeno-associated virus vector harboring DDC, via bilateral intraputaminal infusions, have demonstrated acceptable safety, tolerability, and improvement in motor milestones and cognitive symptoms. ^, The ultimate success of gene therapy in AADC deficiency treatment will depend on a timely diagnosis and the administration of gene therapy before the onset of neurologic damage.

Monoamine Oxidase Deficiency

MAO, encoded by the genes MAOA and MAOB , catalyzes the oxidative deamination of serotonin, epinephrine, and norepinephrine. MAO deficiency is an X-linked disease characterized by clinical manifestations including developmental delay, violent and aggressive behavior, epilepsy, and stereotypic movements. Recent evidence has also suggested that MOA activity in the brain is strongly associated with a greater propensity for aggression.

Dopamine β-Hydroxylase Deficiency

DBH catalyzes the conversion of dopamine to norepinephrine. Dopamine beta hydroxylase (DBH) deficiency is an autosomal recessive disorder secondary to mutations in the DBH gene. DBH-deficiency leads to undetectable CSF/plasma/urine levels of norepinephrine, epinephrine and their metabolites and increased levels of dopamine in the central and autonomous nervous system and peripheral organs. The key symptom in DBH-deficiency is profound orthostatic hypotension, with surprisingly no clear neurocognitive abnormalities or major sleep disturbances. Typical presenting symptoms are hypotension, hypothermia, and hypoglycemia. DBH-deficiency is a treatable disorder; the metabolic block being able to be bypassed by oral supplementation with L- threo- 3,4-dihydroxyphenylserine (L-DOPS/Droxidopa).

Brain Dopamine-Serotonin Vesicular Transporter Disease (Mutation in SLC18A2)

Brain dopamine-serotonin vesicular transport disease is a rare neurological disease caused by mutations in the vesicular monoamine transporter 2 (VMAT2; encoded by SLC18A2 ), Alteration of VMAT2 results in the defective loading of monoamines into synaptic vesicles and, in turn, a functional deficiency.

In the small number of individuals reported, there has been some diversity of symptomatology. Affected individuals commonly had truncal hypotonia and impaired motor skills. Other symptoms included lack of head control, uncontrolled eye movements, abnormal posturing, tremor, dysdiadochokinesia, dysarthria, dystonia and parkinsonism, as well as oropharyngeal and nasal secretions, extreme sweating, fatigue, poor distal circulation, sleep disruptions, and nasal speech. Neuroimaging and CSF neurotransmitter profiles were normal, urine levels of dopamine and norepinephrine were low, and HVA and HIAA were elevated. Treatment with l -dopa caused deterioration in chorea and dystonia, but pramipexole (a dopamine receptor agonist) produced sustained improvement.

Dopamine Transporter Deficiency Syndrome (Mutation in SLC6A3)

Dopamine transporter deficiency syndrome (DTDS), aka infantile parkinsonism-dystonia, is a rare genetic disorder caused by mutations in the SLC6A3 gene encoding the dopamine transporter (DAT). Defective presynaptic uptake of dopamine from the synaptic cleft results in increased synaptic levels, greater catabolism, and diagnostically raised CSF HVA levels. Clinically, DTDS has several phenotypes: a classic infantile form and atypical juvenile and adult variants. The classic variant begins in early infancy with irritability, feeding problems, hypotonia, hyperkinetic movements (chorea, ballismus, dystonia, orolingual dyskinesia), and oculomotor (oculogyric crises, ocular flutter, and eyelid myoclonus) abnormalities. Over the course of years, movements expand to include severe dystonia-parkinsonism. ^, Patients with atypical variants appear normal during infancy and early childhood, however, subsequently develop hyperkinesia, a variety of movement abnormalities (resting and action tremors, dysarthria, and dystonia), and/or hypokinesia with parkinsonian features (bradykinesia, muscle rigidity, and tremor). ^{, ,} Most affected patients have been unresponsive to a variety of medications and deep brain stimulation, although some dopamine agonists have produced limited improvement.

Succinic Semialdehyde Dehydrogenase Deficiency (4-Hydroxybutyric Aciduria)

Succinic semialdehyde dehydrogenase (SSADH) works in conjunction with GABA transaminase to convert GABA to succinic acid. An SSADH deficiency results in increased concentrations of GABA and γ-hydroxybutyrate (GHB; aka 4-hydroxybutyric acid) ( Fig. 17.3 ). ^, Diagnosis is based on the detection of massive increases of GHB in the urine, plasma, and CSF. CSF levels of GABA and a GABA peptide, homocarnosine, are also elevated. ^, The gene for SSADH, an aldehyde dehydrogenase five family member A1 ( ALDH5A1 ), is located on chromosome 6p22. Pathophysiologically, it is unclear whether clinical symptomatology is due to the elevated GHB, GABA, or other metabolic alterations. ^,

Although SSADH deficiency has a mean age at onset of about 11 months, the diagnosis is often delayed for many years. Clinical features are variable and nonspecific and include intellectual disability, disproportionate language dysfunction, autistic traits, hypotonia, ataxia, aggression, anxiety, hallucinations, hyperactivity, occasionally choreoathetosis, and about half have seizures. ^{, ,} About 10% have a severe phenotype characterized by developmental regression and a variety of movement disorder manifestations. ^, MRI imaging has shown cerebral and cerebellar atrophy and T2 hyperintensities in the globus pallidus, cerebellar dentate nucleus, and subthalamic nucleus, although normal in 40% of cases. Magnetoencephalography shows reduction in the gamma frequency band consistent with GABAergic dysfunction and MR spectroscopy shows elevations in the GABA/NAA ratio in all regions. Treatment is symptomatic, with anticonvulsants and medication for behavior problems. Valproate is contraindicated because it may inhibit any residual SSADH activity. Recent advances in clinical application studies have highlighted several therapeutic prospects including mTOR inhibitors, and a putative GHB receptor antagonist.

Huppke–Brendl Syndrome

Huppke–Brendel syndrome is an autosomal recessive defect of the SLC33A1 gene which codes for an acetyl-CoA transporter (AT-1). This mutation leads to a dysfunction of posttranslational ceruloplasmin modification resulting in a low serum ceruloplasmin and copper levels. Clinically this syndrome begins in infancy with congenital cataracts, sensorineural hearing loss, and severe developmental delay. MRI shows cerebellar hypoplasia and hypomyelination. All affected individuals died between age 10 months and 6 years.

Manganese Transporter Defects and Storage Disorder

Manganese (Mn) is a trace metal with an essential cofactor role for multiple enzymes, including neurotransmitters. ^, Mn deposition in the brain can occur secondary to excess environmental exposure (miners, contaminated water), as well as to inherited defects in Mn transport and metabolism. Patients with severe environmental Mn exposure are at risk for an extrapyramidal syndrome termed manganism, with rigidity, bradykinesia, and dystonia. In addition, accumulation in brain and other organs can also result from inherited genetic defects involving either of the two Mn transporters; efflux transporter (SLC30A10) and uptake transporter (SLC39A14) ^, —both cause basal ganglia toxicity which can lead to a progressive dystonia-parkinsonism syndrome.

Hypermanganeseemia with Dystonia 1 (SLC30A10)

Symptoms beginning in childhood (age 2–14 years) include polycythemia, chronic liver disease, progressive dystonia, spasticity, and an unusual high-stepping “cock-walk” gait. Other symptoms include loss of milestones, motor and cognitive impairment, behavioral changes, dysarthria, tremor, and bradykinesia. Late-onset forms in adulthood typically have an akinetic-rigid parkinsonism with early postural instability. Laboratory findings include increased serum Mn concentrations, polycythemia, reduced iron stores with low ferritin, and high total iron binding capacity. Brain MRI contains T1-weighted hyperintensities in the basal ganglia, and white matter. Polycythemia and liver cirrhosis only occur in the SLC30A10 mutation variant.

Hypermanganeseemia with Dystonia 2 (SLC39A14)

Symptoms usually begin early and cause a rapidly progressive dystonia, parkinsonism, dysarthria, bulbar dysfunction, and T1 hyperintensities in the globus pallidus.

Treatment for Mn accumulation, due to either genetic abnormality, includes lifetime chelation therapy with intravenous disodium calcium EDTA (increases urinary excretion of Mn), iron supplementation (competes with and displaces Mn), and the avoidance of foods high in Mn (nuts, dark chocolate, pumpkin, sesame, cloves, and sunflower seeds). Treatment, if started early, generally leads to a good neurological improvement.

Pantothenate Kinase–Associated Neurodegeneration (PKAN)

PKAN is a rare autosomal recessive disorder due to a mutation in the gene for pantothenate kinase 2 (PANK2 ), a regulatory enzyme in the synthetic pathway for coenzyme A. The enzyme PANK2 catalyzes the cytosolic phosphorylation of pantothenate (vitamin B5), N-pantothenoylcysteine, and pantetheine. ( Fig. 17.5 ). Pathologically it is associated with abnormal iron deposition and high concentrations of lipofuscin and neuromelanin in the substantia nigra pars reticulata and the internal segment of the globus pallidus. ^, The definitive mechanism by which basal ganglia iron uptake is increased in PKAN is unknown, recognizing that systemic and CSF iron levels, as well as plasma ferritin, transferrin, and ceruloplasmin, are normal. Patients homozygous for null mutations in PANK2 have a significantly earlier age of disease onset and progress more rapidly.

PKAN has variable presentations and has been divided into (a) a classic early-onset form, containing 75% of cases, with presentation before age 6 years and a rapidly progressive course, and (b) “atypical forms,” which present at a mean age of 14 years. ^, In the classical form, onset is in early childhood with progressive motor difficulties, personality changes, cognitive decline, dysarthria, and spasticity. Abnormal motor function is typically present but may be delayed for several years. Dystonia is the most common movement disorder (orobuccolingual, truncal, and limb), but rigidity, choreoathetosis, and a resting or action tremor may also be present. Ophthalmologic abnormalities include pigmentary retinal degeneration in about two-thirds of patients, alteration of vertical and saccadic pursuits, progressive loss of peripheral visual fields, and blindness. Patients also develop cognitive dysfunction and seizures may be present. Acanthocytosis has been reported in about 8% of classic patients. The course of the early-onset form is variable and is divided into a rapidly and a slowly progressive type. The rapidly progressive early-onset type has a short transition from spasticity to severe movements with opisthotonus, and death within 1–2 years. In contrast, the more prevalent slowly progressive early-onset type advances at a nonuniform rate with dystonia and spasticity leading to being wheelchair-bound by the teens and death occurring within 20 years.

In the “atypical” late-onset childhood form, patients often have speech defects (palilalia, tachylalia, and dysarthria) as an early sign and develop significant psychiatric symptoms (personality changes, impulsivity, obsessive-compulsive disorder, aggression, episodic outbursts, and depression) and even motor and phonic tics. ^{, ,} Although affected individuals are often described as clumsy, motor involvement (parkinsonism, bradykinesia, dystonia, tremor) is a later feature, and spasticity ultimately limits ambulation. Freezing during ambulation, especially when turning or encountering irregular surfaces, has been described. Subclinical retinal changes may be present. In general, the course of atypical PKAN is less severe and more slowly progressive than the early-onset types.

The diagnosis of PKAN depends on the presence of obligate features: onset in the first 2 decades, progressive course, extrapyramidal symptoms, and classic MRI findings showing hypointense T2-weighted and proton density signal in the globus pallidus and substantia nigra ( Fig. 17.6 ). The presence of a hyperintense area within the hypodense areas, named the “eye of the tiger sign,” is considered almost pathognomonic for PKAN. Hyperdense lesions may be present in presymptomatic patients, but as the disease progresses hypodensities appear and ultimately predominate. ^, In patients with PKAN, 7-Tesla imaging has identified elevated concentrations of iron in the globus pallidus, substantia nigra, and internal capsule; not seen in those with heterozygous mutations. Other findings include abnormal cytosomes in lymphocytes, and sea-blue histiocytes in bone marrow—the latter findings being typical of ceroid-lipofuscin accumulation.

There is no specific treatment for PKAN. Theoretically, in patients with residual PANK2 activity the downstream delivery of phosphopantothenate or products in the coenzyme A pathway might be therapeutic. A trial with pantethine did not significantly improve motor function. Iron chelation therapy with desferrioxamine has not been effective, but response was better with deferiprone. ^, Therapy for movement disorders and spasticity is symptomatic. Oral baclofen has been helpful in early stages, but intrathecal infusion has provided only limited benefit. In 23 PKAN patients, deep brain stimulation improved dystonia and quality of life. Pallidotomy and thalamotomy have produced limited and transient benefit.

PLA2G6-Associated Neurodegeneration (PLAN)

The PLA2G6 (phospholipase A2 group VI) gene encodes for a calcium-independent PLA2, which plays a major role in phospholipid remodeling. Functionally, the enzyme catalyzes the hydrolysis of glycerophospholipids and generates a free fatty acid and lysophospholipid, playing a role in membrane homeostasis through the regulation of phospholipids. PLAN represents a second major NBIA phenotype and has at least three separate, but overlapping, phenotypes including (1) infantile neuroaxonal dystrophy (INAD); (2) atypical neuroaxonal dystrophy; and (3) PLA2G6-related dystonia parkinsonism. MRIs in this group may overlap with that seen in PKAN.

INAD is an autosomal recessive disorder, manifesting between 6 months and 3 years, with a gait disturbance and truncal hypotonia. Onset may occur following an intercurrent infection. Progressive symptoms include motor and sensory impairment, spastic tetraplegia, hyperreflexia, and visual impairment associated with optic atrophy. Seizures are a late manifestation. This is a rapidly progressing disorder with death at the end of the first decade. Electromyography shows denervation and nerve conduction studies a distal axonal sensorimotor neuropathy. MRI demonstrates cerebellar atrophy, claval hypertrophy, and brain iron accumulation within the globus pallidus, dentate nucleus, and substantia nigra.

Atypical form of NAD has an older age at onset with presenting symptoms including gait impairment, ataxia, speech difficulties, and autistic features. ^, The clinical course is relatively stable in early childhood with neurological deterioration in mid-childhood consisting of extrapyramidal manifestations (primarily dystonia), dysarthria, and in later stages spastic tetraplegia. Previously described Karak syndrome is now considered an atypical NAD. MRI shows prominent brain iron accumulation with or without cerebellar atrophy.

PLA2G6-related dystonia Parkinsonism is a rare disorder with a broad range of presentations, mostly occurring in early adulthood. Childhood presentations have initially overlapped with atypical NAD, including development of a movement disorder manifested by dystonia, parkinsonism, and choreoathetosis. MRIs have shown nonspecific changes including cerebral atrophy. Symptoms may temporarily respond to l -dopa.

Mitochondrial Membrane Protein-Associated Neurodegeneration

Mitochondrial membrane protein-associated neurodegeneration (MPAN) is a form of neurodegeneration with brain iron accumulation caused by pathogenic variants in the C19Orf12 gene. Although MPAN mutations involve autosomal recessive biallelic C19orf12 variants, autosomal dominant forms have been described with clinically indistinguishable phenotypes. ^, C19orf12 expression is primarily in the brain, blood cells, and adipocytes with derived proteins located within the mitochondria. The precise function of C19orf12 proteins remains unclear, although a role in lipid metabolism, is proposed. At autopsy, neuropathologic analysis has shown a complex pattern of alpha-synucleinopathy and tauopathy.

Clinically, the mean age of symptom onset is 10 years, with a range of 3–30 years. Frequent symptoms include spasticity, cognitive decline, dysarthria, optic atrophy, tremor, dystonia, psychiatric symptoms, dysphagia, and parkinsonism. ^, About half have a motor axonal neuropathy with muscle atrophy, fasciculations, and EMG changes. Neuroimaging shows brain iron accumulation in the globus pallidus and substantia nigra, hyperintense streaking of the internal medullary lamina of the globus pallidus, and white matter lesions. The parkinsonism may improve with l -dopa but some patients develop l -dopa-related dyskinesia.

Beta-Propeller Protein-Associated Neurodegeneration (BPAN)

Beta-propeller protein-associated neurodegeneration (BPAN) is due to heterozygous or hemizygous germline mutations in the X-chromosome gene WDR45 . WDR45 belongs to a family of WD40 proteins that interact with phosphoinositides and promote protein–protein interactions with a role in cell cycle control, translational regulation, signal transduction and autophagy. ^, The name beta-propeller is derived from WDR45's seven-bladed tertiary structure. BPAN is an X-linked dominant neurodegenerative disease and most cases have occurred in females. Typical clinical presentation is in children. Affected children have global developmental delay, epilepsy (multiple seizure types), Rett-like behaviors, stereotypies, dysfunctional sleep, and ocular defects. BPAN with Rett-like features is associated with more epileptic seizures and less deceleration of head growth and breathing irregularities than classic Rett cases with MECP2 variants. Progressive regression occurs in adolescence with the appearance of dystonia, parkinsonian features (bradykinesia, freezing of gait, rigidity), progressive dyskinesia, and dementia. Early MRI imaging may be normal, but substantia nigra swelling and dentate nucleus T2 hyperintensity are early manifestations. Iron deposition in the globus pallidus and substantia nigra generally appear with increasing symptoms. On T1-weighted imaging, the substantia nigra/cerebral peduncles have a distinctive hyperintense “halo.” Parkinsonian symptoms have improved with l -dopa, but medication-induced dyskinesia is common.

Hereditary Ferritinopathy (Neuroferritinopathy)

Neuroferritinopathy is an autosomal-dominant disorder characterized by mutations in the ferritin light-chain gene ( FTL) , which codes for ferritin light polypeptide, on chromosome 19q13. Ferritin plays an important role as the major iron sequestration and storage protein. It is composed of both light (FTL) and heavy chain subunits that possess complementary iron-handling functions. Along with hereditary aceruloplasminemia (HA), it is classified as an adult onset NBIA syndrome. The mean age of onset is 40 years, and presentations have been highly variable. In some it presents as a movement disorder with possible tremor, cerebellar signs, chorea, dystonia, prominent oromandibular dyskinesias, and parkinsonism. ^, Others have neurocognitive features that include dementia, depression, emotional lability, and acute psychosis. ^, Patients have a low serum ferritin level, and the MRI shows abnormal hypointense T2 signal intensity in the globus pallidus and putamen, even early in the disease. With disease progression, hypointensity expands into the substania nigra, dentate nucleus, and cortex.

Hereditary Aceruloplasminemia

HA is a rare autosomal recessive disorder caused by mutations in the gene encoding ceruloplasmin gene (CP ). More than 70 mutations have been reported, and this disorder is often confused with Wilson's disease; both having extremely low levels of ceruloplasmin and overlapping imaging results. In contrast to Wilson's disease, however, aceruloplasminemia is a disorder of iron metabolism due to its activity as an iron oxidase and its absence resulting in iron accumulation within the brain, liver, and pancreas. Clinical manifestations usually occur in adulthood (fifth–sixth decade) with adult-onset refractory anemia, diabetes mellitus, retinal degeneration, and neuropsychiatric symptoms. Progressive neurological problems include dystonia, dysarthria, bradykinesia, rigidity, cerebellar ataxia, and deterioration of cognition and behavior. A few cases with seizures have been described. Neurological symptoms are thought to be secondary to massive iron overload within the basal ganglia, thalamus, and dentate nucleus. Anemia is associated with low serum iron and transferrin saturation, but elevated serum ferritin is usually present. MRI shows hypointensities in the basal ganglia, dentate, and thalamus. Attempts to treat with iron chelators have been disappointing.

Kufor–Rakeb Syndrome

Kufor–Rakeb syndrome (KRS) is a rare autosomal recessive disorder associated with various mutations in the ATP13A2 gene. Mutations in this gene alter the production of a transmembrane protein that regulates intracellular iron metabolism and protects cells against cytotoxicity due to iron accumulation. Clinical symptoms are heterogeneous but often begin in adolescence with parkinsonism, that initially responds to l -dopa. Eye movement abnormalities include slow saccades and supranuclear vertical gaze palsy. Pyramidal signs, including spasticity, increased deep tendon reflexes, and Babinski signs, are common. Cognitive decline has a variable severity and action myoclonus and seizures have been reported. Like other NBIAs, iron accumulation in the basal ganglia has been reported.

Fatty Acid Hydroxylase-Associated Neurodegeneration

Fatty acid hydroxylase-associated neurodegeneration (FAHN) is associated with mutations in the fatty acid two hydroxylase ( FA2H) gene. FA2H produces hydroxylated ceramides and participates in myelin formation. ^, Why there is iron accumulation remains unclear. Clinically the disorder is characterized by the childhood onset of gait abnormalities, spastic quadriparesis, ataxia, dystonia, and ocular abnormalities. Cognitive impairment and seizures may also be present Mutations also cause a form of hereditary spastic paraplegia and leukodystrophy. ^, MRI findings, in addition to iron deposition in the globus pallidus, may also include white matter abnormalities, a thin corpus callosum, and supratentorial atrophy.