Jurnal Internasional Gangguan pergerakan mata dan gejala neurologis pada kesalahan metabolisme bawaan akhir-onset – Koens – – Gangguan Gerakan
 GTP – CH – I deficiency
Abnormalities of eye movement in innate metabolic errors 
|Ptosis||Vision Disorders||Oculogyric Crisis||Nystagmus||Saccadic Oscillation (Flutter and Opsoclonus)||Dysmetric||Slow||Ocular Motor Apraxia (Saccade Initiation Deficit)||Fine Editing Disorders||Optokinetic Nystagmus Disorders||Disorders Vestibulo-ocular reflexes||Estimation of Prevalence of Disorders of Eye Movement|
|Niemann-Pick type C||x (V)||x||x||+  Type 1 Gaucher||x|
|Type 2 Gaucher Disease||x||x||x||x||x||+|
|Gaucher Disease type 3||x (H)||x||x||x||x||x||+  Tay-Sachs disease, childish form||x||x (V)  x||+/–|
|Tay-Sachs disease, slow onset||x (V)||x||x||x||x||+/–  Sandhoff's disease||x||x||x||x||x||x||?|
|Lipid metabolic disorders|
|Cerebrotendinous xanthomatosis||x||x||x  +/–|
|Disorders of carbohydrate metabolism|
|Deficiency of transporting glucose type 1||x  x||x||+|
| Disorders of minerals, metals and vitamin metabolism|
|Wilson's disease||x||x||x (V)||x  x||x||x||x||+|
|Hypermanganesemia with dystonia 1||x [1 9659204] x|
|Pantothenate kinase-associated neurodegeneration||x||x||x||x||x||x||x||+/–  Adult dystonia – parkinsonism||x||x||x (V)||x||x||+/–|
|Biotin-thiamine-responsive basal ganglia disease||x||x (V)||x ?|
|Ataxia with vitamin E deficiency||x||x||x||x||x||x||+|
|Disorders of amino acid metabolism|
|Maple Syrup Syrup Disease||x||x||x||x||+/–  Glutaric aciduria type 1||x||x (V)||x||+/–|
|Congenital glycosylation disorder|
|Deficiency of phosphomannomutase 2||x  x||x||x||x||x||x||+|
|Meta disturbances bolism purine or pyrimidine|
|Zellweger spectrum disorders||x||x||x||x||+|
|Dopamine transporter deficiency syndrome||x||x||x||x||x  +|
|Other disorders of dopamine synthesis or transportation a||x||+/–|
|Disorders of energy metabolism|
|Mitochondrial Disease||x||x||x||x (19659204] x||x||x||x||x||x||+|
|Deficiency of E2 pyruvate dehydrogenase||x||x||x (V)||x||?|
- x: Present.
- L-amino decarboxylase decarboxylase Aromatic deficiency, tyrosine hydroxylase deficiency, GTP-CH-I deficiency (dominant and recessive), sepiapterine reductase deficiency, 6-pyruvoyl-tetrahydropterin synthase deficiency, vesicular disease of brain dopamine-serotonin
- (V): Especially vertical. (H): Especially horizontal. (PEO): Progressive external opththalmoplegia.
- +: often. + / -: rarely. ?: unknown.
Late NP-onset – C usually presents with neurological problems. Movement disorders often occur, especially in the form of adolescents and adults. 14 Disorders of eye movements are also an important feature. Vertical supranuclear gaze palsy (VSGP) is a major feature and is present in about 65% of patients. 15 VSGP in patients with NP-C is characterized by vertical paralysis (especially downward) saccade, whereas subtle pursuit is initially spared. 16 The horizontal saccades were originally preserved, but were eventually affected when the disease developed. 17 18 A Home phenomenon occurs when trying vertical saccade: The eye does not move directly up and down, but in the lateral arc (Video 1). 16 19 A similar phenomenon occurs during the horizontal saccade in Gaucher disease. No vestibulo-ocular response abnormalities have been found. 20 Possible treatment with Miglustat. 21
Gaucher type 2 disease (acute neurological form) and type 3 (subacute neurological form)) is a form of neuronopathy from this disruption of lysosome storage. Gaucher type 2 disease is present during infancy and eye movement abnormalities are the initial signs in affected children, including ocular motor paralysis, saccade delay, oculomotor “apraxia,” and strabismus. 22 23  The type of disease 3 Gaucher is present during childhood or adolescence. Movement disorders are common in type 3, especially ataxia and parkinsonism. 24 However, patients often present with (myoclonus) epilepsy and supranuclear gaze palsy which only affect the horizontal view. 25 – 27 Saccade horizons are very slow and may show curved trajectories, while saccade vertical is preserved initially. 28 – 30 Vestibulo-ocular responses may be impaired. 31 Ocular motor apraxia, which actually reflects the abnormal pattern of head movements associated with defects in saccade initiation, is also observed in Gauchers types 2 and 3. 30 32 Similar to NP- C, abnormal saccade patterns can be used to monitor disease progression. 9 33 Gaucher type 1 disease is a chronic non-neurological form; However, subtle saccade delays have been reported in some patients. 22 34 –  36 Enzyme replacement therapy and substrate reduction therapy available. 21
In the form of the early onset of Tay-Sachs disease (GM2 gangliosidosis), motor symptoms often occur. This is caused by motor neuron dysfunction and involvement of cerebellar with ataxia. 37 Eye movement abnormalities are not a classic feature of late Tays Sachs, but subtle chase disorders with square wave jerks (saccadic intrusion), temporary decelerations from saccade, and up-gaze palsy have been described. Normal vestibulo-ocular response. 37 – 40 In the early-onset of Tach-Sachs disease, the vertical view was disrupted by initial and horizontal views later in the disease. 9  Treatment is not available.
The clinical picture of Sandhoff's disease (GM2 gangliosidosis) is similar to Tay-Sachs disease. The form of early childhood is the most common. The late form of onset of Sandhoff's disease is rare and has a milder phenotype. They are often present as complex neurological disorders with ataxia, chorea, tremor, dystonia, or parkinsonism in combination with motor neuron dysfunction. 21 Abnormalities of eye movements include horizontal and vertical eyestrain disorders with nystagmus. 41 –  43 A patient with adult Sandhoff's disease and pendular nystagmus in combination with palatal tremor has been described. 41 Nursing is not available.
Disorders of Lipid Metabolism
Signs abetalipoproteinemia occurs early in life and develops over time. Neurological manifestations resulting from vitamin deficiencies often begin in the first or second decade of life. Low vitamin E can especially cause progressive neurological symptoms that affect the peripheral and central nervous system. Adult patients show malabsorption, steatosis, abnormal liver transaminases, and neurological signs. 21 Typical eye movement abnormalities, including progressive vision disorders are associated with paresis of the medial rectus muscle and characteristic patterns of dissociated nystagmus. The latter consists of a strong nystagmus, but with a limited range of reinforcing eyes, and a less intense, but full range, nystagmus in the abducted eye. Patients complain of reading difficulties and difficulties associated with convergence disorders. Saccade is slow and hypometric. Vestibular nystagmus and optokinetic nystagmus have abnormal or no rapid phases. 44 A low-fat diet by reducing long chain fatty acids and fat-soluble vitamin supplements is recommended. 21
Late-onset cerebrotendinous xanthomatosis is characterized by xanthomas tendons, psychiatric symptoms, and neurological symptoms, including pyramidal, cerebellar, and extrapyramidal signs in the second or third decade of life. 21 45 Patients showed abnormal pursuit, increased saccadic intrusion, saccade multistep, and antisaccade deficits. 46 Chenodeoxycolic acid and statin therapy are effective treatments and can prevent neurological involvement if started early. 21 47 48
Disorders of Carbohydrate Metabolism
Symptoms of deficiency in type 1 glucose transporters usually occur early in life, but can occur in adolescence or adulthood. In the form of late presentation, paroxysmal exercise-induced dyskinesia occurs which mostly manifests as dystonia, chorea, and ballism. Epilepsy was also observed. 49 Eye movement abnormalities are common and may be very characteristic of brief multidirectional paroxysmal episodes of rapid eye movement in combination with head movements in the same direction, a phenomenon called aberrant gaze.  50 Rolling eyes and fluttering, strabismus, opsoclonus, and restrictions on vertical eye movements have also been described. 50 – 52 Early diagnosis is important because this disorder can be treated with a ketogenic diet. 21
Disorders of Minerals, Metals, or Vitamin Metabolism
Often begin in the teenage years. Liver disease is often the presenting sign, but psychiatric and neurological symptoms include movement disorders are also frequent presentations. The Kayser-Fleischer ring, which is the ophthalmological hallmark of Wilson's disease. 21 Abnormalities of eye movements are frequently present. Impaired vertical, but sometimes also horizontal pursuit, selective slowing of downward saccades, and dysmetria of sacred are all reported. 53 – 57 Gaze distractibility cannot be fixed in their patients 58 At least 1 patient with oculogyric crises has been reported on. 59 Treatment is possible with chelation therapy. 21
Adult-onset hypermemia anemia with dystonia 1 is characterized by parkinsonism, whereas is children usually present with dystonia. Bilateral hyperintensities in the basal ganglia and white matter are attuned to accumulation of manganese typically observed on brain imaging. 21 Increased latency of saccades, misdirected antisodes, and multistep saccharides have been observed by one of the authors (AR, personal observations). Chelation therapy and iron supplementation are recommended 21 .
Pantothenate kinase-associated neurodegeneration (or NBIA type 1) is the most common form of neurodegeneration with brain iron accumulation (NBIA). This is reflected in the “eye-of-the-tiger” sign on brain MRI. 60 Late-onset disease occurs during the second or third decade. It is slowly progressive and is characterized by speech problems, movement disorders, and psychiatric symptoms. 61 Horizontal and vertical supranuclear gaze palsy, impaired saccades, abnormal optokinetic nystagmus, and horizontally impaired vestibulo-ocular responses have been described. 62 63 Oculology crisis has been reported in 1 patient. 60 Treatment with Chelation therapy is not effective. 21
Adult-onset dystonia-parkinsonism (NBIA type 2) also belongs to the heterogeneous group of degenerative disorders causing iron accumulation. And have parkinsonism, dystonia and cognitive decline. Ophthalmic features include strabismus, up-gaze palsy, impaired pursuit with saccadic intrusions, and pendular nystagmus. Vestibulo-ocular responses are not impaired. 64 A case of ocular crisis induced by levodopa has been described in a patient with adult-onset dystonia-parkinsonism. 65 Only symptomatic treatment is available. 1945912
The onset of biotin-thiamine-responsive basal ganglia disease is usually during early childhood, but can occur later in life. 21 66 Dystonia and encephalopathy, bilateral external ophthalmoplegia is observed. 67 – 69 Diagnosis is important because of treatment with thiamine and biotin can be life-saving.
Finally, the onset of ataxia with vitamin E can be at any age. Symptoms include ataxia, areflexia, and impaired proprioception. Nystagmus is observed as part of a cerebellar syndrome. Impaired smooth pursuit, slow saccades, ocular motor apraxia, and strabismus have been reported. 9 70  – 72 Treatment with high dose vitamin E supplementation. 72
Disorders of Amino Acid Metabolism
The four clinical subtypes of maple syrup urine disease (MSUD) are described. Classic MSUD presents soon after birth and is a severe and often rapidly lethal disorder. The phenotypes of the other subtypes (intermediate, intermittent, and thiamine-responsive MSUD) are overlapping. Presentation in adulthood is very rare. Patients with MSUD may decompose during catabolic states and develop behavioral changes, nausea, vomiting, and eventually coma attributed to cerebral edema. Movement disorders may also be present. 21 Abnormalities of eye movements that occur in infants and young people with increased eye weakness and voluntary eye movements with absent vestibulo-ocular reflexes 73 – 75 Treatment is with a low-protein diet in combination with a leucine-, isoleucine-, and valine-free amino acid supplement. Emergency treatment is necessary during metabolic stress, such as intercurrent illness. 21
Glutaric aciduria type 1 (GA1) usually begins in childhood, but adult-onset has been reported as well. Catabolic episodes and intercurrent illnesses and putamen, causing severe dystonia. 21 Ocular abnormalities include intraretinal haemorrhages, cataract, and pigmentary retinopathy. 76 A 19-year- old woman with GA1 showed horizontal nystagmus, upward gaze palsy, and paralysis of convergence. 77 haemorrhages that may be present in GA1. 76 Dietary treatment with a low-lysine diet and Carnitine supplementary damage to the striatum. Similar to MSUD, emergency treatment is necessary to prevent catabolism during periods of fever or prolonged fasting. 21
Congenital Disorders of Glycosylation
Phosphomannomutase 2 deficiency (PMM2-CDG or CDG1A) is the most common congenital disorder of glycosylation. The phenotype is variable, and multiple organs can be involved. 21 CDM PMM2 is diagnosed in childhood, but attenuated forms present later. In adulthood, the symptoms are mild and include ataxia and learning difficulties. 78 A whole range of ocular manifestations can occur and include strabismus, impaired smooth pursuit, nystagmus, ocular flutter, ocular motor apraxia, impaired optokinetic nystagmus , and impaired vestibulo-ocular reflexes. 79 – 82 Strabismus and nystagmus secondary to visual impairment, although they are also described in patients with PMM2-CDG who have normal vision.  78 82 Other subtypes of congenital disorders of glycosylation 1 are common, but also show strabismus and nystagmus. 82 With the subtypes of CDG syndromes , treatment is not available.
three different presentations can be observed: a neonatal infantile, childhood, and adolescent adult presentation. The majority of patients presents in childhood. 84 The phenotype is miller the disease begins in adolescents or adults. Patients have mild to severe cognitive impairment in combination with retinal dystrophy, cataract, glaucoma, hearing impairment, ataxia, pyramidal symptoms, or peripheral neuropathy. 21 Vision is often impaired. 84 Ocular motor abnormalities include hypometric saccades (particularly in the horizontal plane), saccadic intrusion (square-wave jerks), and gaze-evoked nystagmus. 85 Pendular nystagmus can be observed. 86 No curative treatment is available.
Disorders of neurotransmitters, especially those that affect dopaminergic pathways, can cause dystonia with oculogyric crises. Response to low doses of l in some of these diseases is excellent. They can be divided into those that are synthesis, those affecting dopamine transport, and those affecting degradation.
Oculogyric crisis is frequently observed in disorders affecting dopamine synthesis, whereas other abnormalties of eye movements are rare in these disorders.87 Many of these disorders present early in life and, for most of the neurotransmitter disorders, late‐onset presentation is rare. Patients with milder forms of these disorders may remain undiagnosed until adolescence or adulthood, or may be mistakenly diagnosed with cerebral palsy.21 However, recognition of these disorders is important because patients can improve dramatically when treated properly. Most of the late‐onset neurotransmitter disorders are caused by autosomal dominant GTP‐CH‐I deficiency. Patients present with dystonia of the lower limbs that usually progresses to generalized dystonia, although the late‐onset form can also be associated with parkinsonism.88 Autosomal recessive forms of GTP‐CH‐I deficiency have also been described. Oculogyric crises are more frequent in recessive than dominant forms of GTP‐CH‐I deficiency.89–91 Patients with aromatic L‐amino acid decarboxylase deficiency (AADC),2192 tyrosine hydroxylase deficiency,93–96 and 6‐pyruvoyl‐tetrahydropterin synthase deficiency9798 may show oculogyric crisis, in particular in AADC in which oculogyric crisis is one of the key features.9299100 Finally, oculogyric crisis is also described in sepiapterin reductase deficiency.101–103
Disorders affecting dopamine transport include brain dopamine‐serotonin vesicular disease (vesicular monoamine transporter 2 deficiency) and dopamine transporter deficiency syndrome (DAT deficiency). In the latter, adult onset is reported with parkinsonism and psychiatric symptoms.104 Both disorders are associated with oculogyric crisis.87105106 Other abnormalities of eye movements are also observed in DAT deficiency, including saccadic intrusions during smooth pursuit, saccadic oscillations (ocular flutter), slow saccadic eye movements, and ocular motor apraxia.87104107
Energy Metabolism Disorders
Mitochondrial diseases are a group of disorders caused by mutations in mitochondrial DNA (mtDNA; either maternally inherited or de novo) or nuclear DNA (Mendelian inherited). Tissues with high energy needs are commonly affected, including brain, heart, and skeletal muscles. There is a wide range of clinical phenotypes, and onset varies widely. Neurological involvement causes movement disorders, psychomotor retardation or regression, epilepsy, muscle weakness, and migraine.108 Adult onset of mitochondrial disease is especially frequent in disorders caused by multiple deletions in mtDNA, probably attributed to accumulation of mtDNA defects.108 Ocular involvement is frequent, and both central and peripheral causes of eye movements can be present. A well‐known form of ocular motor dysfunction in mitochondrial disease is PEO, characterized by progressive bilateral ptosis and weakness of the extraocular muscles. PEO often occurs in association with other symptoms.109 When it is the sole feature, it is called chronic PEO. PEO is seen in Kearn‐Sayre's syndrome, Pearson's syndrome, and multiple disorders attributed to mitochondrial deletions or point mutations.110 In mitochondrial neurogastrointestinal encephalomyopathy, PEO is characterized by slow and hypometric saccades, particularly for saccades larger than 10 degrees, and abducting saccades are slower than adducting saccades.111 Central eye movement disorders are observed in patients with Leigh's syndrome (subacute necrotizing encephalomyelopathy). Patients with early‐onset disease show disorders similar to those attributed to thiamine deficieny, including gaze‐evoked nystagmus, impaired vestibular responses, internuclear ophthalmoplegia, and upbeat nystagmus switching to downbeat nystagmus during convergence.9112 A combination of PEO with central eye movement disorders has been described in POLG‐related disorders. The phenotype of POLG‐related disorders is variable; it ranges from severe and often lethal childhood forms to later‐onset forms with a continuum of overlapping phenotypes, including ophthalmoplegia.113 In addition to ophthalmoplegia, ptosis, gaze‐evoked nystagmus, rebound nystagmus, abnormalties of saccades (dysmetria and slowing), and impaired pursuit have been observed.114 Treatment of mitochondrial diseases is still limited and includes vitamins and cofactors.21
Pyruvate dehydrogenase deficiency is divided into different subtypes. An adult patient diagnosed with pyruvate dehydrogenase E1 deficiency showed parkinsonism, impaired up gaze, and jerky horizontal eye movements during pursuit.115 Pendular nystagmus, eye rolling, and ocular motor apraxia are reported in children with pyruvate dehydrogenase E2 deficiency.116 The disease can be treated with a ketogenic diet, thiamine, L‐carnitine, and α‐lipoic acid.117
We have reviewed IEM in which the onset of symptoms can occur relatively late in life and in which ocular motor abnormalities can be a prominent sign. Recognition of these patterns of abnormalities of eye movements is important because they may be the key to accurate early diagnosis and thus to a timely start of treatment. Unfortunately, there continues to be a lack of information about eye movement disorders in many IEMs because little attention is given to them in daily practice. Examination of the vestibular system, in particular, is neglected in most studies even though it often provides essential information about localization and diagnosis. Disorders of hearing are commonly recognized in many IEMs, but vestibular function is rarely commented upon. A standard, focused examination of the different subtypes of eye movements (range of motion, gaze‐holding, saccades, pursuit, and vestibular responses) can be performed relatively quickly in most patients during routine physical examination. Testing with video‐oculography has also become more user‐ and patient‐friendly and helps to quantify the eye movement abnormalities, making these abnormalities a valuable biomarker for following the natural course of disease or the response to therapies.
(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique.
L.H.K.: 1A, 1B, 1C, 3A, 3B
M.A.J.T.: 1A, 1B, 3B