ptosis

Nanophthalmos 3

Clinical Characteristics
Ocular Features: 

A six generation Chinese family has been reported in which 12 affected members had small eyes, ptosis, apparent enophthalmos, shallow anterior chambers, and small corneas.  Hyperopic refractive errors ranged from +6.00 to +11.25 (mean +8.25).  

Systemic Features: 

None reported.

Genetics

The transmission pattern for this 6 generation family strongly suggests autosomal dominant inheritance.  No mutation has been identified but the 2q11-14 locus is strongly associated with the phenotype.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Treatment has not been reported but monitoring for narrow angle glaucoma is advised.

References
Article Title: 

Retinopathy with Neutropenia

Clinical Characteristics
Ocular Features: 

Pigmentary retinopathy was reported in a 25 year old female with moderately reduced visual acuity. Rare bone spicules pigment deposits were present in the periphery and macular edema was noted. Severely reduced scotopic and photopic responses were recorded.

Systemic Features: 

The single reported individual had congenital neutropenia and microcephaly. She had evident growth retardation and microcephaly at birth with subsequent recurrent upper respiratory infections and gingivitis. Speech and motor development were normal. Short stature was noted as well. The limbs were described as slender as in Cohen syndrome (216550) but no truncal obesity or joint hypermobility was present. The facial dysmorphism only vaguely resembled that found in Cohen syndrome (216550).

Genetics

This is a newly described condition whose unique identity remains to be established since only a single patient has been reported. This patient carried two heterozygous splicing mutations in the same VPS13B gene, the same gene in which more than 100 homozygous mutations have been found in individuals with Cohen syndrome (216550). Each parent carried a different splicing mutation in VPS13B.

Cohen syndrome (216550) however, has additional phenotypic features such as truncal obesity, intellectual disabilities, intermittent neutropenia, microcephaly, facial dysmorphism, myopia, and progressive chorioretinal dystrophy. Variable amounts of neutropenia were observed from age 5 years but the marrow was normocellular in appearance.

Isolated retinopathy with neutropenia may or may not be an autosomal recessive variant of Cohen syndrome (216550).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

External Ophthalmoplegia, Facial Weakness, and Malignant Hyperthermia

Clinical Characteristics
Ocular Features: 

A subset of patients with malignant hyperthermia susceptibility (MHS) secondary to mutations in RYR1 has congenital ophthalmoplegia and ptosis.   Magnetic resonance imaging may reveal hypoplasia of extraocular muscles and intraorbital cranial nerves.

Systemic Features: 

The weakness in extraocular and levator muscles is sometimes associated with more generalized myopathy of a variable degree.  The myopathy may be progressive and individuals with extensive skeletal muscle weakness may have respiratory insufficiency and scoliosis. The clinical spectrum is broad and there is no consistent pattern in the degree of skeletal muscle weakness associated with ocular muscle involvement.  This may be explained in part by the variety of myopathies found among patients with mutations in RYR1 such as:  central core disease, multiminicore disease, congenital fiber type disproportion, centronuclear myopathy, and nemaline myopathy.

Malignant hyperthermia due to mutations in RYR1 is most commonly inherited as an autosomal dominant trait precipitated by exposure to certain volatile anesthetic agents such as halothane, isoflurane, and enflurane used in association with succinylcholine during general anesthesia.  Patients may experience acidosis, muscle rigidity, rhabdomyolysis and tachycardia with arrhythmias.  Myoglobinuria may lead to renal failure.

Exercise-induced heat stress rarely precipitates malignant hyperthermia.

Genetics

Ptosis, ophthalmoplegia, and susceptibility to malignant hyperthermia can occur as separate heritable conditions and it is uncommon for them to coexist as in the MHS1 syndrome described here.  Due to the heterogeneous signs of muscle disease reported among and between families, it is likely that MHS1 consists of more than one disorder.  Mutations in RYR1 are commonly associated with susceptibility to malignant hyperthermia while the co-occurrence of skeletal muscle disease is inconsistent and involvement of extraocular muscles is even rarer.

There is good evidence that at least 6 types of MHS exist.  A large number of responsible mutations in 2 genes, RYR1 (19q13.2) and CACNA1S (1q32.1), have been identified and there is good evidence that at least 4 additional loci exist.  Mutations in RYR1 are responsible for MHS1 and account for approximately 70% of susceptible individuals.  Families with both autosomal dominant and autosomal recessive inheritance patterns have been reported.  

It is not understood why some families with MHS1 have ocular and skeletal muscle abnormalities while others do not.  External ophthalmoplegia is most often secondary to mutations in mitochondrial DNA but the importance of presurgical recognition of the risk of malignant hyperthermia suggests that pre-surgery gene screening for RYR1 in such patients is warranted.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

The best treatment is prevention by using alternate anesthetic agents if the risk is recognized preoperatively.  Temperature should be monitored in all patients undergoing general anesthesia since prompt recognition of hyperthermia is essential.  Inhalation agents and succinylcholine must be discontinued and dantrolene sodium should be given promptly.  Metabolic abnormalities must be corrected and both external and internal body cooling should be initiated immediately.  Intravascular coagulation is an additional risk and coagulation profiles should be obtained.

A positive family history of MHS requires pre-anesthesia gene testing but failure to detect a mutation in known genes does not rule out susceptibility.

Ptosis surgery may be helpful in selected patients.

References
Article Title: 

Recessive RYR1 mutations cause unusual congenital myopathy with prominent nuclear internalization and large areas of myofibrillar disorganization

Bevilacqua JA, Monnier N, Bitoun M, Eymard B, Ferreiro A, Monges S, Lubieniecki F, Taratuto AL, Laquerriere A, Claeys KG, Marty I, Fardeau M, Guicheney P, Lunardi J, Romero NB. Recessive RYR1 mutations cause unusual congenital myopathy with prominent nuclear internalization and large areas of myofibrillar disorganization. Neuropathol Appl Neurobiol. 2011 Apr;37(3):271-84.

PubMed ID: 
21062345

Optic Atrophy, Ophthalmoplegia, Myopathy, and Neuropathy

Clinical Characteristics
Ocular Features: 

Visual symptoms have an insidious onset in childhood with vision loss and progressive external ophthalmoplegia.  Ptosis may be evident later.  The optic atrophy is progressive.   ERG abnormalities have been reported but no pigmentary retinopathy has been seen.  Myopia is sometimes present.

Systemic Features: 

The extraocular signs and symptoms are variable and generally have a later onset.  Some patients have an early onset of sensorineural hearing loss.  Muscle cramps and hyperreflexia may occur with clonus and a spastic gait.  Ataxia seems to be common.  The neurological phenotype has been likened to muscular sclerosis, Kearns-Sayre syndrome, and spastic paraplegia.  Muscle biopsies show variable-sized and atrophic fibers.

Genetics

This is generally considered an autosomal dominant disorder secondary to mutations in the OPA1 gene.  It is allelic to optic atrophy 1 (165500) but may also be the same condition since the p.Arg247His mutation has been found in patients with both disorders.  This syndromic form of optic atrophy may also result from biallelic mutations in OPA1 in which the clinical disease is more severe and earlier in onset. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is available for the neurological disease but low vision aids should be considered to selected patients especially during childhood educational activities.

References
Article Title: 

Multi-system neurological disease is common in patients with OPA1 mutations

Yu-Wai-Man P, Griffiths PG, Gorman GS, Lourenco CM, Wright AF, Auer-Grumbach M, Toscano A, Musumeci O, Valentino ML, Caporali L, Lamperti C, Tallaksen CM, Duffey P, Miller J, Whittaker RG, Baker MR, Jackson MJ, Clarke MP, Dhillon B, Czermin B, Stewart JD, Hudson G, Reynier P, Bonneau D, Marques W Jr, Lenaers G, McFarland R, Taylor RW, Turnbull DM, Votruba M, Zeviani M, Carelli V, Bindoff LA, Horvath R, Amati-Bonneau P, Chinnery PF. Multi-system neurological disease is common in patients with OPA1 mutations. Brain. 2010 Mar;133(Pt 3):771-86.

PubMed ID: 
20157015

Myasthenic Syndromes, Congenital, Including AChR Deficiency

Clinical Characteristics
Ocular Features: 

The congenital myasthenic syndromes are genetically and clinically heterogeneous.  Ptosis is the outstanding ocular sign and virtually always present.  Strabismus and ophthalmoplegia are less common.  These signs are not helpful in the differential diagnosis of the many types of congenital myasthenia.

Some degree of ptosis is usually evident during the first 6 months of life.  By about 2 years of age strabismus and ophthalmoparesis are apparent but this sequence is highly variable.

Systemic Features: 

This is a group of nonprogressive disorders most often associated with acetylcholine receptor (AChR) defects at the neuromuscular junction.  An early sign may be decreased fetal movements.  Generalized weakness, a weak cry, and hypotonia are evident at birth.  Easy fatigability and limb weakness are noted in early childhood and affected children have difficulty running. Facial weakness, dysarthria, weakness of the tongue, and dysphagia are often present and many patients have respiratory difficulties. Motor development can be delayed.  Acute illnesses may exacerbate muscle weakness.

Genetics

This is the most common form of the congenital myasthenic syndromes. It is an autosomal recessive disorder of the postsynaptic type, so called because the mutations occur in genes that encode the subunits of acetylcholine receptors: CHRNE(17P13.2), and CHRNB1(17p13.1).  A similar phenotype results from mutations in MUSK (9p31.3) which is critical for synaptic differentiation.

Mutations in RAPSN(11p11.2), whose protein product is important for stabilization of the acetylcholine receptors at the endplate, may result in a similar phenotype but may also produce the fetal akinesia deformation sequence.  This lethal condition is often associated with severe respiratory disease and dysmorphism including limb contractures, micrognathia, and feeding difficulties.  Nothing is known about the ocular signs.

Another autosomal recessive congenital myasthenic syndrome (610542), CMSTA1, has a somewhat later onset (adolescence) and weakness in a limb girdle distribution but no ptosis or oculomotor problems.  Tubular aggregates of muscle fibers can be seen on biopsy.

Presynaptic autosomal recessive forms of congenital myasthenia such as CMS20 (617143) caused by mutations in SLC5A7 (2q12) and CMS21 (617239) secondary to mutations in SLC18A3 (10q11.23) with severe episodic apnea and ocular signs of ptosis and ophthalmoparesis have been reported.

Other postsynaptic forms of congenital myasthenia are the fast-channel type (FCCNS) (608930) and the slow channel type (SCCMS) (601462).  Ophthalmoparesis occurs early in both types.

The classification of congenital myasthenia syndromes is under construction.  In the case of many types only a single or very few families have been reported.   While the clinical manifestations involve alterations in the neuromuscular junnction, some result from heterozygous mutations while others are due to homozygous changes.  The defect may reside in presynaptic, synaptic, or postsynaptic mechanisms.  For a discussion and comprehensive listing of the various types see 601462.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Cholinesterase inhibitor drugs can be highly beneficial in some forms of the disease but genotyping is necessary before attempting pharmacological therapy.  Frequent ventilation and enteric feeding may be helpful for selected individuals.  Individuals should be protected from acute illnesses, especially respiratory infections.

References
Article Title: 

Impaired Presynaptic High-Affinity Choline Transporter Causes a Congenital Myasthenic Syndrome with Episodic Apnea

Bauche S, O'Regan S, Azuma Y, Laffargue F, McMacken G, Sternberg D, Brochier G, Buon C, Bouzidi N, Topf A, Lacene E, Remerand G, Beaufrere AM, Pebrel-Richard C, Thevenon J, El Chehadeh-Djebbar S, Faivre L, Duffourd Y, Ricci F, Mongini T, Fiorillo C, Astrea G, Burloiu CM, Butoianu N, Sandu C, Servais L, Bonne G, Nelson I, Desguerre I, Nougues MC, Boeuf B, Romero N, Laporte J, Boland A, Lechner D, Deleuze JF, Fontaine B, Strochlic L, Lochmuller H, Eymard B, Mayer M, Nicole S. Impaired Presynaptic High-Affinity Choline Transporter Causes a Congenital Myasthenic Syndrome with Episodic Apnea. Am J Hum Genet. 2016 Sep 1;99(3):753-61.

PubMed ID: 
27569547

Congenital myasthenic syndromes

Hanta?O D, Richard P, Koenig J, Eymard B. Congenital myasthenic syndromes. Curr Opin Neurol. 2004 Oct;17(5):539-51. Review.

PubMed ID: 
15367858

Craniofacial-Deafness-Hand Syndrome

Clinical Characteristics
Ocular Features: 

This rare syndrome has anomalies in periocular structures but not in the eye itself.  The lid fissures are downward slanting with telecanthus and hypertelorism.  The nasolacrimal duct was missing in several individuals.

Systemic Features: 

The midface is generally flat with underdeveloped maxillary bones and absent or small nasal bones but there may be frontal bossing.  The nose appears hypoplastic with a broad, flat root resulting in dystopia canthorum.  Micrognathia and a high arched palate are sometimes present.   The sinuses are often underdeveloped.  There may be ulnar deviation of the hands and fingers while flexion contractures and clinodactyly of the 5th finger are often present.  A sensorineural hearing loss is present in many individuals.  No poliosis has been reported.

Genetics

This is an autosomal dominant condition secondary to mutations in the PAX3 gene (22q36.1) in at least some patients.  Changes in the same gene are responsible for types 1 and 3 of the Waardenburg syndrome (193500, 148820).  In fact, the major mutation, a heterozygous C-to-G transversion, has been identified in the same codon in both CDHS and Waardenburg 3 (148820) patients.

More patients need to be genotyped to clarify the clinical features distinctive of Waardenburg types 1 and 3 (193500, 148820) and CDHS syndrome.  Should we consider these conditions allelic or simply the result of variable expressivity?  The appearance of the nasal root and associated structures is similar and both conditions are associated with sensorineural hearing loss.  Type 3 Waardenburg syndrome (148820) often has a cleft palate and musculoskeletal deformities of the upper limbs and fingers.  So far, no pigmentation changes have been reported in CDHS.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Surgical release of contractures could be considered.

References
Article Title: 

Spastic Paraplegia 7

Clinical Characteristics
Ocular Features: 

Many but not all individuals have significant visual loss due to optic atrophy.  Other ocular signs include supranuclear palsy, ptosis, and nystagmus.  Older individuals with advanced disease may have progressive external ophthalmoplegia.

Systemic Features: 

There is a great deal of clinical heterogeneity between families and not all individuals have severe neurological disease.  Progressive neurological signs (primarily abnormal gait) are often present in late childhood or early adolescence but may occur late in life.  Clinical features include muscle atrophy and weakness with spasticity (more pronounced in the lower limbs), ataxia, pyramidal signs, dysphagia, and cerebellar dysarthria.  Hyperreflexia and extensor plantar responses are often present.  Cognitive deficits are manifest as deficits in attention and higher levels of reasoning.  Some patients have a mild peripheral neuropathy with decreased vibratory sense.  Many patients have significant dysfunction of the bladder sphincter.  Adults may lose their mobility and are confined to a wheelchair.

Some patients develop scoliosis and pes cavus.  The MRI often shows cerebellar and mild frontal cortical atrophy.

Genetics

This type of spastic paraplegia results from mutations in the paraplegin gene, SPG7 (16q24.3).  It is usually transmitted in an autosomal recessive pattern although heterozygous patients with symptoms have been reported. Evidence suggests that the symptoms arise from a defect in mitochondrial respiration.

Patients with spastic paraplegia 15 (270700) have a similar neurological phenotype plus a flecked retina.  Congenital cataracts are part of the phenotype of spastic paraplegia 46 (614409).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment is symptomatic.  Physical, speech, and occupational therapy may be helpful in selected patients.  Low vision aids may be of benefit in some individuals, at least early in the disease.

References
Article Title: 

Mutations in the SPG7 gene cause chronic progressive external ophthalmoplegia through disordered mitochondrial DNA maintenance

Pfeffer G, Gorman GS, Griffin H, Kurzawa-Akanbi M, Blakely EL, Wilson I, Sitarz K, Moore D, Murphy JL, Alston CL, Pyle A, Coxhead J, Payne B, Gorrie GH, Longman C, Hadjivassiliou M, McConville J, Dick D, Imam I, Hilton D, Norwood F, Baker MR, Jaiser SR, Yu-Wai-Man P, Farrell M, McCarthy A, Lynch T, McFarland R, Schaefer AM, Turnbull DM, Horvath R, Taylor RW, Chinnery PF. Mutations in the SPG7 gene cause chronic progressive external ophthalmoplegia through disordered mitochondrial DNA maintenance. Brain. 2014 Apr 10. [Epub ahead of print].

PubMed ID: 
24727571

A clinical, genetic, and biochemical characterization of SPG7 mutations in a large cohort of patients with hereditary spastic paraplegia

Arnoldi A, Tonelli A, Crippa F, Villani G, Pacelli C, Sironi M, Pozzoli U, D'Angelo MG, Meola G, Martinuzzi A, Crimella C, Redaelli F, Panzeri C, Renieri A, Comi GP, Turconi AC, Bresolin N, Bassi MT. A clinical, genetic, and biochemical characterization of SPG7 mutations in a large cohort of patients with hereditary spastic paraplegia. Hum Mutat. 2008 Apr;29(4):522-31.

PubMed ID: 
18200586

Joubert Syndrome and Related Disorders

Clinical Characteristics
Ocular Features: 

Ocular findings like systemic features are highly variable both within and between families.  Vision can be normal but in other patients it is severely reduced to the range of 20/200.  The pupils may respond sluggishly or even paradoxically to light.  ERG recordings have been reported to be normal in some patients, but absent or reduced in others.  The fundus appearance is often normal but in other individuals the pigmentation is mottled, the retinal arterioles are attenuated, and the macula has a cellophane maculopathy.  Drusen and colobomas are sometimes seen in the optic nerve while occasional patients have typical chorioretinal colobomas.  The eyebrows are often highly arched.

The oculomotor system is frequently involved.  Apraxia to some degree is common with most patients having difficulty with smooth pursuit and saccadic movements.  Compensatory head thrusting is often observed.  A pendular nystagmus may be present while esophoria or esotropia is present in many patients.

Systemic Features: 

There is a great deal of clinical heterogeneity in this group of ciliary dyskinesias.  Developmental delays, cognitive impairment, truncal ataxia, breathing irregularities, and behavioral disorders are among the more common features.  Hyperactivity and aggressiveness combined with dependency require constant vigilance and care.  Postaxial polydactyly is a feature of some cases.  Hypotonia is evident at birth.  Liver failure and renal disease develop in many individuals.  Neuroimaging of the midbrain-hindbrain area reveals agenesis or some degree of dysgenesis of the vermis with the 'molar tooth sign' in the isthmus region considered to be a diagnostic sign.  The fourth ventricle is usually enlarged while the cerebellar hemispheres may be hypoplastic.

The facies features are said to be distinctive in older individuals.  The face appears long with frontal prominence due to bitemporal narrowing, the nasal bridge and tip are prominent, the jaw is prominent, the lower lip protrudes, and the corners of the mouth are turned down.

Genetics

This is a clinically and genetically heterogeneous group of disorders with many overlapping features.  Most disorders in this disease category, known as JSRD, are inherited in an autosomal recessive pattern.  Mutations in at least 34 genes have been identified.  One, OFD1 (300804), is located on the X chromosome (Xp22.2).

There are significant clinical similarities to Meckel syndrome (249000) and Smith-Lemli-Opitz syndrome (270400).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment is mostly for specific symptoms such as respiratory distress, renal disease, speech and physical therapy, low vision, and hepatic failure.

References
Article Title: 

Joubert Syndrome: Ophthalmological Findings in Correlation with Genotype and Hepatorenal Disease in 99 Patients Prospectively Evaluated at a Single Center

Brooks BP, Zein WM, Thompson AH, Mokhtarzadeh M, Doherty DA, Parisi M, Glass IA, Malicdan MC, Vilboux T, Vemulapalli M, Mullikin JC, Gahl WA, Gunay-Aygun M. Joubert Syndrome: Ophthalmological Findings in Correlation with Genotype and Hepatorenal Disease in 99 Patients Prospectively Evaluated at a Single Center. Ophthalmology. 2018 Jul 25. pii: S0161-6420(18)30686-9. doi: 10.1016/j.ophtha.2018.05.026. [Epub ahead of print].

PubMed ID: 
30055837

Ophthalmological findings in Joubert syndrome

Sturm V, Leiba H, Menke MN, Valente EM, Poretti A, Landau K, Boltshauser E. Ophthalmological findings in Joubert syndrome. Eye (Lond). 2010 Feb;24(2):222-5.

PubMed ID: 
19461662

Coloboma, Ptosis, Hypertelorism, and Global Delay

Clinical Characteristics
Ocular Features: 

The ocular phenotype includes ptosis, hypertelorism, iris coloboma and prominent epicanthal folds with epicanthus inversus.  The coloboma may be unilateral and involve other portions of the uveal tract. The orbits have been described as shallow.  At least one patient has been described as having microphthalmia and microcornea.

Systemic Features: 

The systemic features reported include severe global delay, a broad nasal bridge, and short stature.  Physical growth delay, mental retardation, short neck, low-set ears, and low posterior hairline have been noted.  Males may have a micropenis and undescended testicles.  The pinnae may be malformed and rotated posteriorly. Several patients had a hearing deficit.

CT scans have shown microcephaly with pachygyria and or even virtual agyria of the frontal, temporal, and parietal lobes.

Genetics

This condition is caused by heterozygous mutations in the ACTG1 gene (17q25.3) and therefore transmitted in an autosomal dominant pattern.  Sibs but no parental consanguinity has been reported.  Both sexes are affected.

Mutations in the same gene are responsible for a somewhat similar condition known as Baraister-Winter 2 syndrome (614583).

Temtamy syndrome (218340) has some similar features but is caused by mutations in C12orf57 (12p13).  In addition to microphthalmia and colobomas, intractable seizures, global delay and abnormalities of the corpus callosum are present.

Several patients that may have had this syndrome have had pericentric inversions of chromosome 2: inv(2)(p12q14).  The PAX8 gene maps to the distal breakpoint of this inversion and may play a role as the location of a recessive mutation or as part of a submicroscopic inversion.  No parent-child transmission has been reported.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 

Exome sequencing identifies compound heterozygous mutations in C12orf57 in two siblings with severe intellectual disability, hypoplasia of the corpus callosum, chorioretinal coloboma, and intractable seizures

Platzer K, Huning I, Obieglo C, Schwarzmayr T, Gabriel R, Strom TM, Gillessen-Kaesbach G, Kaiser FJ. Exome sequencing identifies compound heterozygous mutations in C12orf57 in two siblings with severe intellectual disability, hypoplasia of the corpus callosum, chorioretinal coloboma, and intractable seizures. Am J Med Genet A. 2014 May 5. [Epub ahead of print].

PubMed ID: 
24798461

Pearson Marrow-Pancreas Syndrome

Clinical Characteristics
Ocular Features: 

Although systemic disease is usually evident during infancy, ocular symptoms such as ptosis and ophthalmoplegia may not be apparent until adulthood in those that survive.  The ocular myopathy in adults can resemble Kearns-Sayre syndrome (530000) as the result of a phenotypic shift from a predominantly hematopoietic disorder to a mitochondrial myopathy.  Bilateral zonular cataracts and strabismus have been reported in a 3 year old male.  A midperiphery pigmentary retinopathy has been observed.  Endothelial cell failure leads to corneal edema. 

Systemic Features: 

Low birth weight, failure to thrive, hypoplastic anemia and exocrine pancreatic dysfunction are often seen in infancy.  Precursor cells in the marrow show typical vacuolization. Malabsorption and insulin-dependent diabetes often develop.  The pancreas and bone marrow may become fibrotic.  Patients with the classic syndrome as a child can develop features of the Kearns-Sayre syndrome if they survive childhood.  Progressive muscle weakness in pharyngeal, facial, neck, and limb muscles is sometimes seen in older individuals and muscle biopsy reveals ragged-red fibers characteristic of mitochondrial disease.  Some patients have an organic aciduria and others develop hepatic failure with elevated transaminase, bilirubin and lipid levels.  Kidney damage results in Fanconi syndrome.  Young children may recover from the refractory anemia eventually but metabolic acidosis with life-threatening lactic acidosis is a constant threat and responsible for many childhood deaths.

Genetics

Deletions in mtDNA involving numerous genes are responsible for this condition.  As a result, it is maternally transmitted but somewhat inconsistently due to mitochondrial heteroplasmy.  Both sexes are affected.  The irregular size of the mtDNA deletions and the tissue distribution of affected mitochondria results in considerable variation in clinical expression.  Defective oxidative phosphorylation seems to be the underlying cause of many of the signs and symptoms.

Treatment
Treatment Options: 

This multisystem disease requires careful monitoring throughout life.  Blood transfusions may be required and careful attention needs to be given to nutrition and metabolic dysfunction.  A few patients have required insulin.  In spite of vigorous treatment of electrolyte imbalances, correction of acidosis, and hormonal supplements, many patients do not survive beyond childhood.  Organ failure requires individualized treatment.

References
Article Title: 

Pearson Syndrome

Farruggia P, Di Marco F, Dufour C. Pearson Syndrome. Expert Rev Hematol. 2018 Jan 16. doi: 10.1080/17474086.2018.1426454. [Epub ahead of print].

PubMed ID: 
29337599

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