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Case Records of the Massachusetts General Hospital

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Case 38-2017: A 20-Year-Old Woman with and Progressive

Florian S. Eichler, M.D., Kathryn J. Swoboda, M.D., Ann L. Hunt, D.O., Dean M. Cestari, M.D., and Otto Rapalino, M.D.​​

Presentation of Case

From the Departments of Dr. Andrew J. Cole (Neurology): A 20-year-old woman was seen in the neurology (F.S.E., K.J.S., A.L.H.) and Radiology (O.R.), clinic of this hospital because of seizures and progressive dystonia. Massachusetts General Hospital, the De‑ partments of Neurology (F.S.E., K.J.S., The patient had been well until she was 3 years of age, when she began to have A.L.H.), Ophthalmology (D.M.C.), and recurrent falls, difficulty walking, and seizures. A diagnostic evaluation at an- Radiology (O.R.), Harvard Medical School, other hospital included a muscle biopsy, electroencephalography, and electroretinog- and the Department of Ophthalmology, Massachusetts and Ear Infirmary raphy, as well as analysis of the carnitine profile, visual-evoked potentials, and (D.M.C.) — all in Boston. the enzymatic activity of the mitochondrial respiratory chain; the test results were N Engl J Med 2017;377:2376-85. reportedly interpreted as inconclusive. Magnetic resonance imaging (MRI) of the DOI: 10.1056/NEJMcpc1706109 head was performed; T2-weighted images reportedly showed areas of abnormal Copyright © 2017 Massachusetts Medical Society. hyperintensity in the bilaterally. Therapy with carbamazepine and a multivitamin was initiated. During the next 15 years, progressive stepwise deteriora- tion, including worsening dystonia and dysarthria, occurred; cognitive function was not affected. Exacerbations of her neurologic decline were precipitated by acute intercurrent illnesses and recurrent seizures from which she did not have complete recovery. Five years before the current presentation, anticonvulsant medications were stopped for 1 month. During that period, three flurries of generalized tonic– clonic seizures occurred. During admission to a second hospital, the complete count, oxygen saturation, blood levels of calcium and magnesium, and results of liver- and renal-function tests were normal. Medications on discharge included carbamazepine, l-carnitine, , and vitamin B complex. On follow-up at that hospital 2 months later, the patient reportedly had dysarthria, dystonic posturing of both arms (especially the hands), and an ataxic gait. Strength was 3+/5 in the distal arms and 5/5 in the proximal arms. Approximate- ly 2.8 years before the current presentation, the patient was evaluated at a third

hospital. MRI of the head was performed; T2-weighted and fluid-attenuated inver- sion recovery (FLAIR) images again showed areas of abnormal hyperintensity in the basal ganglia bilaterally, with mild associated volume loss. The MRI was sig-

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nificantly degraded by susceptibility artifacts showed nonenhancing areas of abnormal, diffuse that were produced by orthodontic braces. The hyperintensity in the cerebral cortex, basal gan- blood lactate level was 1.6 mmol per liter (14.4 glia, thalami, midbrain, and . Repeat mg per deciliter; reference range at this hospi- imaging studies obtained 10 months later showed tal, 0.5 to 2.2 mmol per liter [4.5 to 19.8 mg per resolution of most of the signal abnormalities, deciliter]), and the (CSF) although residual signal abnormalities and vol- lactate level was 1.2 mmol per liter (10.8 mg per ume loss were present in the basal ganglia. deciliter; reference range at this hospital, 0.6 to On examination at this hospital, which was 2.2 mmol per liter [5.4 to 19.8 mg per deciliter]). performed with the assistance of an interpreter, A preliminary diagnosis of mitochondrial cy- the patient was alert and her mental status was topathy was made. normal. She had severe dysarthria, but her speech Between 17 and 11 months before the current was fluent, with no paraphasic errors. Cranial- presentation, examinations were performed at nerve function was intact, and visual acuity was the second hospital while the patient was receiv- 20/30 in both . She had fluctuating dystonia ing levetiracetam and trihexyphenidyl. Speech of the hands, arms, legs, and feet that was more difficulties, limb rigidity, and spasticity of the prominent on the left side than on the right side. left upper leg were noted. She was referred to the Strength was normal throughout. The plantar re- clinic of this hospital. flex was extensor in the left foot and was mute in On presentation to this hospital, the patient the right foot; deep-tendon reflexes were normal. reported dysarthric speech and painful dystonia The gait was slow, wide-based, and dystonic, of her hands and limbs (particularly her legs). with inversion and internal rotation of both feet. The dystonia was associated with gait deteriora- The remainder of the examination was normal. tion that had led to use of a wheelchair. Cognitive MRI of the head was performed without the function was not affected. Her most recent sei- administration of intravenous contrast material.

zure had occurred 1 year before this assessment. T2-weighted images showed persistent areas of The patient was the fourth child of healthy abnormal hyperintensity, volume loss, and sub- consanguineous parents (first cousins). She had tle abnormal mineralization in the basal ganglia been born after a full-term gestation, with no bilaterally. Electroencephalography, which was complications. Her birth weight was 3750 g. performed while the patient was awake and Medications were levetiracetam, pyridoxine, thia- while she was asleep, revealed excessive, diffuse mine, and trihexyphenidyl. She had no known beta activity, with no definitive evidence of epi- allergies. She lived with her family in the Arabian leptiform abnormalities. Peninsula; she spoke Arabic and some English, The younger sister was present during the attended a regular high school, and did not drink clinic visit and was also examined. She had mild alcohol, smoke tobacco, or use illicit drugs. dystonia of the right foot, an extensor plantar She had three older brothers who were healthy. reflex in the right foot, and a clumsy gait. She had a 6-year-old sister with a similar illness Dr. Ann L. Hunt: The patient was referred to the that had started when she was 3 years of age, movement disorders clinic of this hospital (see when she had an episode of bloody and Video 1, available with the full text of this article A video showing then began to have dystonia of the right foot, at NEJM.org). She came to the visit in a wheel- the examination difficulty walking, and seizures. On evaluation chair. Her speech was dysarthric in both English is available at NEJM.org at that time, the sister had a peak blood lactate and Arabic. She had previously been a fluent Arabic level of 11.7 mmol per liter (105.4 mg per deciliter) speaker. While the patient was sitting quietly, and a peak CSF lactate level of 2.3 mmol per liter she had dystonic posturing of the left hand and (20.7 mg per deciliter). Genetic testing for the both feet. During any activation procedure, the MELAS syndrome (mitochondrial encephalomy- dystonic posturing of the left hand and left foot opathy, , and strokelike episodes) increased. During rapid successive movements, and the was reportedly negative, slowness and dystonic posturing were more and levels of urinary organic acids were normal. prominent in the left hand and foot than in the The sister underwent MRI of the head during the right hand and foot. There was no rigidity of the

acute phase of her disease. T2-weighted images arms or legs. When she walked, dystonic postur-

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A B C

D E F

Figure 1. Patient’s MRI Studies.

An axial fluid‑attenuated inversion recovery (FLAIR) image, a coronal T2‑weighted image, and an axial T2‑weighted image were obtained approximately 2.8 years before the current presentation (Panels A, B, and C, respectively). The images show areas of abnormal hyperintensity in the basal ganglia bilaterally (arrows). An axial FLAIR image and a coronal T2‑weighted image were obtained on presentation (Panels D and E, respectively). The images show evidence of mild volume loss, with a slight increase in ventricular size. An axial susceptibility‑weighted image (Panel F) shows bilateral areas of mineralization in the basal ganglia (arrows).

ing was more prominent in the left hand and nence of the lateral ventricles) and abnormal foot than in the right hand and foot. A pull test mineralization of the basal ganglia (as com- revealed good postural stability. pared with the mineralization in age-matched A diagnostic test was performed. controls). The patient’s sister had undergone MRI twice: Differential Diagnosis approximately 3.5 years before the patient’s cur- rent presentation (when the sister was 3 years of Dr. Otto Rapalino: MRI had been performed ap- age) and approximately 2.8 years before the cur- proximately 2.8 years before the current presen- rent presentation. The initial MRI (Fig. 2A, 2B,

tation (Fig. 1A, 1B, and 1C), and T2-weighted and 2C) showed extensive signal abnormalities in and FLAIR images had shown areas of abnormal the deep gray matter (including the basal ganglia hyperintensity in the basal ganglia bilaterally, and thalami), cerebral cortex, cerebral white without associated abnormal restricted diffusion. matter, cerebellum, and brain stem. Many of MRI was next performed on the patient’s presen- these areas had abnormal restricted diffusion, tation to this hospital (Fig. 1D, 1E, and 1F), and and there was subtle, nonspecific enhancement the images showed similar bilateral, symmetric in the basal ganglia. Proton magnetic resonance signal abnormalities in the basal ganglia, as well spectroscopy was also performed at that time as progressive volume loss (with slight promi- (Fig. 2F) and showed scattered lactate peaks in

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A B C

D E F

10,000

5000

0

–5000

–6950 4.30 3.71 3.09 2.48 1.87 1.25 0.64

Figure 2. Sister’s MRI Studies.

An axial FLAIR image, an axial T2‑weighted image, and an axial diffusion‑weighted image were obtained approxi‑ mately 3.5 years before the patient’s current presentation, when the sister was 3 years of age (Panels A, B, and C, respectively). The images show extensive areas of abnormal hyperintensity and restricted diffusion involving the cortex, subcortical white matter, and deep gray matter bilaterally. Proton magnetic resonance spectroscopy (Panel F), which was performed with the use of a multivoxel technique (echo time, 95.7 ms), shows prominent lactate peaks (arrow). An axial FLAIR image and an axial T2‑weighted image were obtained approximately 2.8 years before the cur‑ rent presentation (Panels D and E, respectively). The images show mild generalized parenchymal volume loss, with a slight increase in ventricular size.

the brain parenchyma, without a notable decrease seizures, and episodic deterioration. She had in the ratio of N-acetylaspartate to creatine or a consanguineous parents and an affected sister. notable increase in the ratio of choline to creatine. MRI revealed abnormal mineralization in the The follow-up MRI (Fig. 2D and 2E) showed basal ganglia. Her sister had more diffuse ab- resolution of most of the diffuse supratentorial normalities. In addition, it is important to note

and infratentorial abnormalities, although T2- the absence of cognitive, hearing, and vision weighted images showed residual hyperintensity problems and of dysmorphic features. in the basal ganglia (findings similar to those seen in the patient). Dystonia Dr. Florian S. Eichler: In summary, the patient The main feature of this patient’s presentation is was a 20-year-old woman with normal cognitive dystonia, which is a that is function who presented with progressive fluctu- characterized by sustained or intermittent mus- ating dystonia. She had symptoms that went be- cle contractions that cause abnormal and often yond developmental delay, including dysarthria, repetitive movements or postures (or both). The

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movements and postures are typically twisted, hearing and vision problems would be atypical involve muscle groups in a distinct pattern or in a patient with . sequence, and may be tremulous. In this patient, they were precipitated by acute concurrent ill- Disorders with Involvement of the Basal nesses. Ganglia Dystonia is typically classified according to In the initial workup, the results of screening the patient’s age at onset, the pattern of involve- laboratory tests and CSF analysis were normal, ment, and the temporal pattern.1 In this patient, and MRI of the head revealed abnormal miner- dystonia occurred in childhood, was manifested alization in the basal ganglia. The sister also by multifocal limb rigidity, and resulted in parox- had involvement of the caudate, putamen, and ysmal events. Because the patient and her sister on her initial imaging studies. It is were both affected, an inherited disorder seems important to note that the sister had a ribbon likely. of cortical involvement and some subcortical In considering inherited disorders that cause involvement but had sparing of the central white progressive and paroxysmal dystonia, we must matter. The swelling of critical affected struc- first identify whether the patient had only dysto- tures also seems to be an important clue. nia or had dystonia plus other symptoms. Patients Recognition of patterns on MRI of the head with often have only dystonia can often aid in the diagnosis of a neurologic and ; those with paroxysmal or intermit- condition.4 Symmetric involvement of the basal tent dystonia have brief episodes of dystonia and ganglia, which was seen in this case, can be seen return to normal in between the episodes.2 In in patients who have been exposed to toxins such this patient, the dystonia was associated with as methanol, carbon monoxide, and cyanide. neurologic symptoms, including dysarthria and However, this patient had a progressive course seizures. over a period of years and had no known history Among the inherited disorders that cause dys- of exposure to toxins. Also, a neurocutaneous tonia plus other symptoms, treatable disorders cause of progressive dystonia seems unlikely, given — such as an inherited defect of dopamine syn- the absence of telangiectasias and other skin thesis and Wilson’s disease — are generally ruled findings. Lysosomal disorders, such as Tay–Sachs out first. In this case, there is no mention of disease and fucosidosis, can involve the basal treatment with levodopa and carbidopa (Sinemet); ganglia, but the pattern seen on MRI is different a positive effect of such treatment would suggest a from the pattern seen in this case and the symp- dopamine defect. There is also no mention of an toms generally do not fluctuate. abnormal blood copper or ceruloplasmin level, a Other disorders that result in symmetric in- Kayser–Fleischer ring, or another ocular abnor- volvement of the basal ganglia are those caused mality due to copper excess, findings that would by with brain iron accumula- suggest Wilson’s disease. tion.5 Patients with such disorders generally have In assessing for hereditary causes of dystonia, hypointensity in the caudate, putamen, and thala-

it can be helpful to determine the pattern of in- mus on T2-weighted images, whereas this patient

heritance: autosomal recessive, autosomal domi- had hyperintensity on T2-weighted images, so nant, X-linked recessive, or mitochondrial.2 In the these disorders are unlikely. Among the many patient’s family, the condition is not present in mitochondrial disorders that can affect both successive generations, and therefore, the disor- white matter and deep gray matter, a defect of der is most likely recessive or mitochondrial. aminoacyl transfer RNA synthetases is a pos- Unfortunately, this does not narrow the differ- sibility.6 Such a defect can result in thalamic ential diagnosis tremendously. However, the epi- swelling, brain-stem involvement, and increased sodic fluctuation in symptoms suggests a mito- lactate levels, findings that were seen in this chondrial disease.3 Other features that suggest a case; however, the absence of prominent white- mitochondrial disease include the seizures, extra- matter involvement in this case makes this pos- pyramidal symptoms, involvement of the basal sibility unlikely. ganglia on MRI, and lactate peaks on proton Which diseases are associated with little or magnetic resonance spectroscopy. The absence of no white-matter involvement and such selective

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vulnerability to nuclei in the deep gray matter? in the basal ganglia and mineralization in SUCLA2 and SUCLG1, which cause on MRI. These features were seen on follow-up depletion of mitochondrial DNA, are associated imaging in this patient. with hyperintensity in the caudate and putamen The imaging findings are consistent with the

on T2-weighted images and lactate peaks on pro- clinical impression and, in my mind, clinch the ton magnetic resonance spectroscopy.7 However, diagnosis of BTBGD. Because the c.1264A→G problems with overall growth, vision, and hear- in SLC19A3 is the most common mis- ing commonly occur with these mutations and sense mutation among families from Saudi Arabia, were absent in this case. I suspect that this is the disease-causing muta- The most common mitochondrial disorder tion in this case. that is associated with progressive neurodegen- eration and involvement of the basal ganglia and Imaging Differential Diagnosis brain stem is the Leigh syndrome,8 which is a subacute necrotizing encephalomyelopathy that Dr. Rapalino: The patient and her sister had strik- can be caused by any one of almost 100 identi- ingly similar abnormalities on MRI of the head fied genes. A prominent form of the Leigh syn- and a relatively early onset of these abnormalities, drome is caused by de- features that suggest an inborn error of metabo- ficiency, which results in a fluctuating disease lism.11 The possibility of due to a course, lactate accumulation, and involvement of toxin (e.g., carbon monoxide, methadone,11 viga- the basal ganglia, findings that were seen in this batrin, methanol,12 or cyanide13) is considered to case. However, results of initial genetic testing be unlikely because the sisters had no known for the Leigh syndrome were reportedly normal, history of exposure to toxins. The preferential as were levels of urinary organic acids. involvement of the basal ganglia and cerebral cortex during the acute phase, with residual sig- Biotin––Responsive Basal Ganglia nal abnormalities that predominantly affect the Disease basal ganglia during the chronic phase, can be Several disorders can cause the Leigh syndrome.9 compatible with a relatively broad imaging-based There is no mention of a difficult perinatal de- differential diagnosis,11,14 including mitochon- livery, which would suggest , drial disorders (particularly the Leigh syndrome), or hyperbilirubinemia, which would suggest ker- BTBGD, organic acidurias (particularly glutaric nicterus. Also, a diagnosis of aciduria and methylmalonic aciduria), maple syrup seems unlikely, given the symptoms seen in this urine disease, , Wilson’s patient. However, biotin–thiamine–responsive disease, osmotic demyelination, hypoglycemic en- (BTBGD), which is due to cephalopathy, hypoxic–ischemic encephalopathy, a mutation in SLC19A3, may be a good fit. viral (e.g., due to Epstein–Barr virus, The patient is of Arab descent, and BTBGD is flavivirus, or influenza A), autoimmune disorders most commonly detected in families from Saudi (e.g., acute disseminated or Arabia. In affected patients, the age at onset is postinfectious causes), and other conditions usually 3 or 4 years, seizures occur frequently, a (Table 1). The results of proton magnetic reso- movement disorder is usually triggered by febrile nance spectroscopy are helpful in narrowing this illnesses, and speech is often impaired; all these differential diagnosis, because there was no ab- features were seen in this patient. normal elevation of glutamate or glutamine, During the acute phase of BTBGD, patients abnormal branched-chain amino acids, or other have signal changes and swelling in the basal abnormal metabolites.37 The chronic and slowly ganglia (both the caudate and the putamen) on progressive course of the disease process also 10 T2-weighted images, as well as diffuse involve- argues against many infectious causes. On the ment of cortical, subcortical, and infratentorial basis of the findings on MRI and proton mag- brain structures and sparing of white-matter netic resonance spectroscopy, the differential diag- structures. These features were seen on initial nosis can be narrowed to either a mitochondrial imaging in the patient’s sister. During the chron- disorder or BTBGD. ic phase of BTBGD, patients have atrophy and Dr. Cole: With Dr. Rapalino’s help, we concluded

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Table 1. Imaging-Based Differential Diagnosis.*

Condition Key Findings on Imaging Studies Genetic Biotin–thiamine–responsive basal ganglia disease15 Symmetric abnormalities in the cerebral cortex, subcortical white ­matter, basal ganglia, thalami, cerebellum, and brain stem on ­initial MRI; atrophy and necrosis of the basal ganglia on follow-up MRI; rare involvement; lactate peaks on proton MRS Leigh syndrome and Leigh-like syndrome16,17 Symmetric abnormalities in the basal ganglia, thalami, brain stem, cerebellum, and spinal cord on MRI; possible necrosis due to ­parenchymal changes; lactate peaks on proton MRS HIBCH mutations18 Necrosis in the basal ganglia (similar to that seen in the Leigh syn‑ drome) on MRI Glutaric aciduria types I and II19,20 in the globi pallidi and cerebral white matter on MRI; caudate nucleus may be spared, edema can result in neostriatal necrosis, and sylvian fissures can have a “bat-wing” appearance Methylmalonic, propionic, isovaleric, and 3-methylglutaconic Abnormalities in the basal ganglia on MRI, followed by necrosis acidurias21,22 SUCLA2 and SUCLG1 mutations and ETHE1 mutations23 Abnormalities on MRI similar to those seen with organic acidurias and mitochondrial disorders NUP62-related disorder24 Neostriatal edema on MRI, followed by necrosis Maple syrup urine disease25,26 Diffuse abnormalities in the cerebellar white matter, dorsal brain stem, cerebral peduncles, internal capsules, basal ganglia, and thalami on MRI Sulfite oxidase and molybdenum cofactor deficiency27 Neostriatal signal abnormalities and edema on MRI Alexander disease type I28,29 Abnormalities in the white matter and basal ganglia on MRI Wilson’s disease30,31 Prolongation in the basal ganglia, thalami (often ventrolateral), cor­ tical and subcortical structures, brain stem, vermis, and dentate nuclei and restricted diffusion on MRI Acquired metabolic Hepatic encephalopathy32,33 Abnormalities in the basal ganglia, cortex, and white matter and re‑ stricted diffusion on MRI Hypoglycemic encephalopathy32,33 Signal abnormalities in the cortex, hippocampi, corpus callosum, ­basal ganglia, and cerebral white matter and restricted diffusion on MRI Hypoxic–ischemic encephalopathy32 Involvement of the deep gray matter, cortex, hippocampi, and cere­ bellum on MRI; brain-stem involvement is less common Hemolytic–uremic syndrome34 Microthrombosis of the basal ganglia, thalami, hippocampi, and ­cortex on MRI Osmotic demyelination syndrome33 Usually pontine involvement on MRI, but extrapontine or basal ­ganglia involvement can also be seen Infectious and postinfectious Acute necrotizing encephalopathy of childhood (e.g., due to Symmetric lesions in the putamina, thalami, brain stem, and white influenza A, herpes simplex virus, or mycoplasma)35 matter on MRI (e.g., due to Epstein–Barr virus, herpes simplex Variable involvement of the deep gray matter, cortex, and white matter virus, influenza A, or West Nile virus), Japanese encephalitis, on MRI or Creutzfeldt–Jakob disease36 Autoimmune Autoimmune encephalitis (e.g., due to the anti–dopamine 2 receptor Variable findings on MRI; acute disseminated encephalomyelitis and or anti–N-methyl-d-aspartate receptor), acute disseminated post-streptococcal autoimmunity can involve the deep gray matter ­encephalomyelitis, or post-streptococcal autoimmunity bilaterally Toxic Carbon monoxide, methanol, methadone, vigabatrin, cyanide, Potential involvement of the basal ganglia on MRI, but rare in children hydrogen sulfide, organophosphate36 Neoplastic Low-grade glial neoplasms in these regions that simulate non- Usually nonenhancing infiltrative and asymmetrical signal abnormali‑ neoplastic disease ties on MRI

* MRI denotes magnetic resonance imaging, and MRS magnetic resonance spectroscopy.

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that the patient potentially had BTBGD due to In severe cases, symptoms could progress to a mutation in SLC19A3. We referred the patient coma with generalized dystonia, severe cog- and her sister for neuro-ophthalmologic exami- wheel rigidity, and quadriparesis or to death. nation and genetic testing. Symptoms were ameliorated with biotin supple- mentation. This recessive disorder was deter- Clinical Diagnosis mined to be caused by mutations in SLC19A3, which encodes the thiamine transporter Biotin–thiamine–responsive basal ganglia disease THTR2.39 Since the genetic cause of BTBGD was due to a mutation in SLC19A3. initially identified, an increasingly broad pheno- typic spectrum associated with mutations in SL- Dr. Florian S. Eichler’s C19A3 has emerged, ranging from a severe in- Diagnosis fantile-onset Leigh syndrome (with rapidly progressive, diffuse and charac- Biotin–thiamine–responsive basal ganglia dis- teristic lesions in the thalami, basal ganglia, and ease due to a mutation in SLC19A3, most likely brain stem on MRI) to a milder adult-onset en- c.1264A→G. cephalopathy similar to that caused by insuffi- cient dietary intake of thiamine.10,40-44 Neuro-Ophthalmologic Testing THTR2 is expressed in the intestine, liver, and brain. In contrast, expression of THTR1, a Dr. Dean M. Cestari: On neuro-ophthalmologic ex- second thiamine transporter, is limited to sys- amination, the best corrected visual acuity was temic tissues. At concentrations lower than 2 20/25+2 in the right eye and 20/20− in the left mM, thiamine requires active transport across eye. There was no dyschromatopsia or relative membranes. However, at higher concentrations, afferent pupillary defect. The anterior segment thiamine can diffuse passively across mem- and intraocular pressures were normal in both branes. , the active eyes. Humphrey visual-field testing showed dif- form of thiamine, is a critical cofactor for a fusely decreased sensitivity on the total deviation number of that are involved in energy plot that was more prominent in the left eye metabolism, including the α-ketoacid dehydro- than in the right eye, but the results were unreli- genase complexes (for mitochondrial energy able in both eyes (with a 38% false negative rate metabolism), transketolase (through the pentose in the left eye and a 37% false negative rate in phosphate pathway), and 2-hydroxyacyl coen- the right eye). A dilated fundus examination re- zyme A lyase (for peroxisome α-oxidation).45 Bio- vealed small yellowish flecks in the macula and tin metabolites are involved in expression of peripheral retina in both eyes (Fig. 3) that ap- multiple enzymes in metabolism and peared to be concentrated in the fovea. Optical affect other genes and pathways, and thus biotin coherence tomography revealed that these flecks were distributed within the retina and not in the retinal pigment epithelium. Ductions and ver- sions were full. There was no ptosis, proptosis, or .

Genetic Testing and Management

Dr. Kathryn J. Swoboda: BTBGD (Online Mendelian Inheritance in Man number, 607583) was first recognized as a novel syndrome that occurred during childhood and affected families in Saudi Figure 3. Photograph of the Patient’s Left Optic Nerve Arabia.38 Affected children had a gradual onset and Macula. of encephalopathy, which could be accompanied Small, nonreflective, yellowish intraretinal flecks are by seizures, dysarthria and , supranu- distributed throughout the fovea and peripheral retina. clear facial palsy, and external ophthalmoplegia.

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intake and thiamine intake are synergistic in en- ergy metabolism is suspected. These cofactors suring energy metabolism, particularly in situa- are typically part of a cocktail that includes addi- tions that involve catabolic states.46 Furthermore, tional B vitamins and coenzyme Q10. In an acute studies have shown that marginal biotin levels crisis, higher doses of thiamine may be provided result in down-regulation of SLC19A3 expression.47 intravenously. In some cases, fever may be con- Given that BTBGD overlaps phenotypically trolled with additional treatment with Sinemet with other causes of the Leigh syndrome and and anticonvulsant therapy. Early diagnosis and given the risk of missing a treatable metabolic treatment are associated with normal develop- encephalopathy in the context of a prolonged mental outcomes, whereas later diagnosis results diagnostic process, next-generation panel testing in a wide range of mild-to-moderate neurologic or exome sequencing, performed in parallel with deficits and intellectual disabilities. A higher mitochondrial genomic sequencing, is the best frequency of episodes of acute crises before the approach to ensure a rapid and accurate diag- diagnosis correlates with poorer outcomes, but nosis. In rare situations in which there is an immediate treatment with biotin and thiamine increased incidence of specific founder mutations can completely eliminate recurrence of crises.40 in a given population, targeted Sanger sequencing Dr. Cole: With Dr. Hunt and Dr. Katherine Sims remains a feasible and cost-effective alternative. (Neurology), we monitored the patient for approxi- In this patient and her sister, diagnostic testing mately 3 months after the initial diagnosis, while with an 88-gene panel for the Leigh syndrome Sinemet was administered and physical therapy and nuclear mitochondrial encephalopathy con- was provided. There was some reduction in the firmed the presence of a homozygous c.1264A→G dystonia and improvement in ambulation. The (p.Thr422Ala) mutation in SLC19A3. patient then began to receive a regimen of biotin (200 mg three times daily) and thiamine (200 mg Discussion of Management twice daily), with instructions to continue these treatments for the rest of her life. She returned While awaiting confirmation of the genetic diag- home, and we have had no further follow-up. nosis, treatment with vitamin cofactor supple- mentation that includes thiamine and biotin helps Final Diagnosis to prevent further irreversible neurologic injury and, in mild cases, could result in complete Biotin–thiamine–responsive basal ganglia disease resolution of symptoms. Daily treatment with a due to a homozygous c.1264A→G (p.Thr422Ala) combination of thiamine (20 mg per kilogram mutation in SLC19A3. of body weight per day) and biotin (10 mg per This case was presented at Neurology Grand Rounds. kilogram) is a prudent approach in a patient who Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. may have the Leigh syndrome (including BTBGD) We thank Drs. Thomas Byrne and Khaled Moussawi (Neurol- or in a patient in whom a related defect in en- ogy) for assistance with organizing the conference.

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