Danilo's Page

We saw the ophthalmologist this morning. She will do surgery to fix his strabismus in a month or two. Meanwhile we have to be very diligent in using his eye drops and patch to get the vision up a little more in that eye before the surgery. The date of the surgery will depend on whether that start him on IVIG or not, but the gears are set in motion.

Next Thursday we will see Dr. Mitchell.

Dr. P just called me. I am disappointed only because the results still aren't conclusive. He said that the spinal tap showed "he doesn't have all of the OMS markers". He has "unconventional T-cell markers", but not "increased B-cells" which is the telltale sign of OMS.

He feels that the case for mitochondrial disease is weak, but he wants to wait for that gene panel to come back which will be 6-8 weeks. That would definitely rule out (or rule in?) the hereditary spinocerebellar ataxias. He is also going to see if they have enough of the muscle biopsy left to do some gene mapping or something.

He is also going to call Dr. N and he asked what kind of reception he thought he would get. I told him I want him to be the head neurologist so he will work with the local docs.

I guess if the hereditary stuff is ruled out, he wants to try Danilo on IVIG which is the intravenous immunoglobins.

Soooo ..... he will call us when the results come in.

By the way, Danilo is doing better every day. He has been walking around without holding onto things since we came back from Springfield. Oh, and to better describe Danilo's eye movements, his eyes do not "flit". Imagine a black marble in a small see-through plastic box not much bigger than the marble. Now, shake the box.

We met with Dr. Pranzatelli on Wednesday along with Liz Tate, the nurse practitioner with whom we've been communicating, and another research assistant named Tyler. Dr. P questioned Oge thoroughly about Danilo's illness and Danilo was given a long examination that was videotaped. As scheduled, Danilo was given another spinal tap, so a special "immunophenotyping" test could be performed. I didn't take very good notes, but the following are some of the matters discussed. We were left feeling very hopeful.

1.Dr. P should be calling Oge in the next few days with the results from the spinal tap.

Danilo's symptoms were the same as many other OMS patients. They will look for elevated T cells and two kinds of B cells in the spinal fluid. Dr. P will determine what drugs to use in treatment depending on what shows up. Danilo could be a "borderline" case. (I think he meant if the spinal tap test results don't clearly show more than the usual antibodies…or something) In some borderline cases, Dr. P will administer treatment and see if the patient responds to confirm an OMS diagnosis.

2.There was some question at first about whether Danilo's weird eye movements towards the beginning of his illness were true opsoclonus. However, we viewed footage of patients with OMS and Danilo’s eye dance was more or less the same.

I had remembered Danilo's eye movements as being somewhat on a horizontal line, but Oge remembered them as more random directions and in little circles.Obviously Oge spent more time watching this phenomenon. Apparently there is a fine distinction between nystagmus (regular frequency and on one plane) and opsoclonus (random) and they can mean different things.

In examining Danilo, they saw one opsoclonus-like flit of his eyes upward. Oge still sees Danilo's eyes flit when he's tired. It's less dramatic opsoclonus, but it's there.

3.Dr.P is doing more tests and re-doing some tests. DNA tests should be back in 6-8 weeks to rule out the 14 hereditary Spinocerebellar Ataxias. He's doing an antigliadinal test to look for another autoimmune disease that's somehow similar to OMS. He's reviewing the mitochondrial test records that Niparko ordered and may call the labs with follow up questions. He's redoing a test from months ago that showed something abnormal about Danilo’s thyroid. A urine test that showed a possible abnormality (or a diet high in some fruits) will be redone once Oge can get Danilo to give up another sample.

4.This may not be totally accurate account of what he said, but I think Pranzatelli indicated doubt that Danilo has a hereditary ataxia. I think he said since most of the hereditary ataxias are progressive and Danilo isn't getting worse, they don't look likely.

5.We'll see how the tests turn out, but it felt like Dr. P was leaning toward the OMS diagnosis based on the symptoms. We watched tapes of OMS kids and, though I'm no expert, the way they moved looked a hell of a lot like the way Danilo moves. (The people I've met with hereditary ataxias so far at the ataxia support group move differently, not as shaky with the hands)

The tapes showed dramatic before and after treatment video. Kids with tremors and ataxia worse than Danilo's were running around after treatment. Treatment takes years and relapses can happen. However, some patients improve immediately upon receiving treatment.

We felt good about Dr. P's attention to detail and thoroughness in questioning. I thought it was intriguing that he asked if Danilo was the only left handed individual in the family.

One of the workers at the Ronald MacDonald house told me she's seen people come from all over the world, including South Africa and Germany, to see Dr. Pranzatelli. So, that made me feel we were in the right place.

Wednesday night we met a woman and her son who is finishing up treatment with Dr. P. for OMS and is now healthy. They live out of state also. Oge talked to her at length and received important information regarding Dr. Mitchell's approach.(Mitchell is the OMS specialist in L.A.who Danilo is seeing in a couple of weeks)

Depending on how things go, Oge can keep Dr. P. as Danilo's doctor if Danilo has OMS because he is willing to work with another physician here to administer treatment. Also, he trains parents to inject one of the steroids often used in treatment (Oh goody).

Incidentally, Danilo got a prescription for a special walker and it arrived this week.

That's it for now.

Flight Information:

Southwest Flight 1131 M
Tuesday, January 20 - LOS ANGELES INTL(LAX) to CHICAGO-MIDWAY(MDW)
Depart LOS ANGELES INTL(LAX) at 07:05AM and
Arrive in CHICAGO-MIDWAY(MDW) at 12:55PM

ATA Flight Number: 3323 *
Flight Date: JAN-20-2004 400PM - 500PM
Departs: CHICAGO (Midway)
Arrives: SPRINGFIELD
Seats: 12A 12B 12C
--------------------------------------------------
ATA Flight Number: 3328 *
Flight Date: JAN-22-2004 935AM - 1035AM
Departs: SPRINGFIELD
Arrives: CHICAGO (Midway)

Southwest Flight 327 M
Thursday, January 22 - CHICAGO-MIDWAY(MDW) to LOS ANGELES INTL(LAX)
Depart CHICAGO-MIDWAY(MDW) at 02:15PM and
Arrive in LOS ANGELES INTL(LAX) at 04:50PM

800-I-FLY-ATA
http://ata.custhelp.com

From the evening of Jan.20th through morning of Jan. 22nd.,we'll be at

Ronald McDonald House Charities of Central Illinois.
610 North Seventh Street
Springfield, IL 62702
Office: 217/528-3314
Fax: 217/528-6084
E-mail: contact@rmhccentralil.org
http://www.rmhccentralil.org/contact.cfm

During the day of Wednesday,Jan 21st, we'll be at:

The National Pediatric Myoclonus Center
SIU, School of Medicine
Dept. of Neurology, Div. of Pediatric Neurology
Springfield, IL 62794-9643
office: 217-545-7635
fax: 217-545-1903

Georgetown University Medical Center
Institute For Molecular and Human Genetics
Molecular Diagnostic Laboratory
Phone: 202-444-1750 fax 202-444-1770

Specimen type: muscle

Test: Mitochondrial DNA Mutation Analysis

Method: Point mutations were analyzed by multiplex PCR amplification of the relevant segments of the mitochondrial genome followed by dot blot and hybridization with ASO (allele specific oligonucleotide) probes. Mitochondrial DNA deletions and rearrangements were detected by Southern blot analysis. The predominant mitochondrial DNA mutations are:

[Deleted table with details.If anyone's interested, email smittelbach at hotmail.com -sjm]

Results: point mutations and deletions were not detected

Interpretation: Test results should be interpreted in the context of patient’s clinical and family history.

Point mutations or deletions were not detected. We cannot confirm the diagnosis of mitochondrial DNA disorders. If a mitochondrial DNA disorder is still hypothesized, we can perform more extensive mutation analysis. A clinical summary that includes indications of a mitochondrial disorder must be provided. Mother’s blood specimen is required for further analysis.

(Signed)
Lee-Jun C. Wong, Ph.D., FACMG
Director, Molecular Diagnostic Laboratory, IMHG
ABMG Certified, Clinical Molecular Genetics
CLIA License: 09D0644931
3800 Reservoir Road NW, M4000, Washington DC 20007 Tel 202-444-1750
Fax 202-444 1770

Athena Diagnostics
Four Biotech Park
377 Plantation Street
Worcester, Massachusetts 01605
www.athenadiagnostics.com
800-394-4493
508-756-2886
Patient: Danilo Vargas

Specimen type: Muscle
Test Category: Diagnostic (Symptomatic)
Test requested: Mitochondrial Enzyme Deficiency Myopathy Panel
Requesting Physician: Krieger, Mark
Report to: Children’s Hospital/Pathology and Lab Medicine
Address: 4650 Sunset Blvd.,Mailstop 32, Los Angeles, CA 90027
Diagnosis Service Report

Interpretation
This individual possesses normal mitochondrial respiratory enzyme activities with mitochondrial proliferation. Although the likelihood that this individual is affected with a defect in the respiratory chain has been significantly reduced, this individual may possess an underlying mitochondrial disease.

Technical Results
Respiratory Enzymes Reference Range umol/min/gm tissue Result
Cytochrome c oxidase >1.41 2.34
Succinate-cytochrome c reductase >0.35 0.91
Rotenone-sensitive NADH cytochrome c reductase >0.52 1.14
NADH dehydrogenase >14.22 20.58
Reference Enzymes
Succinate dehydrogenase >0.47 1.58
Citrate synthase 7.33-12.43 16.98

Protein (total) >30.00 63.80


Methods
Biochemical analysis for mitochondrial enzyme activities were performed spectrophotometrically. This analysis, as performed here, are greater than 95% accurate. Mitochondrial respiratory enzyme activities are normalized with respect to citrate synthase activity. Reference values are presented as greater than 50% of the normal median or as the normal range. Citrate synthase activity is utilized as a reference marker to evaluate muscle mitochondrial content.

Comments
This analysis indicates that this individual possesses normal mitochondrial respiratory enzyme activities with abnormally elevated citrate synthase activity. This individual’s elevated citrate synthase activity reflects mitochondrial proliferation and may be indicative of mitochondrial disease. Mitochondrial proliferation, particularly in the presence of a strong history of maternal inheritance or clinical features is compatible with mitochondrial DNA mutation.

Mitochondrial DNA mutation analysis of patients’ muscle tissue and/or blood samples is available through Athena Diagnostics. Please contact Client Services 1-800-394-4493 for further information.

References
1.DiMauro, S.et al. In Mitochondrial Disorders in Neurology, Schapira, A.H.U. and DiMauro, S.(eds), Buttersworth-Heinemann, Oxford Press 1994;pp.91-115

2.DiMauro, S. et al. Ann Neurol 1985;17:521-538

3.King, T.E. Methods Enzymol 1967;10:322-331

4.King, T.E.,Howard, R.L. Methods Enzymol 1967; 10:275-294

5.Lowry, O.H. et al. J Biol Chem 1951; 193:265-271

6. Sottocasa, G.L.et al. J Cell Biol 1967;32:415-439

7.Srere, P.A. Methods Enzymol 1969; 13: 3-11

8. Wharton, D.C., Tzagoloff, A. Methods Enzymol 1967; 10: 245-250

(Signed) William K. Seltzer, PhD, FACMG, Laboratory Director
Sat Dev Batish, PhD, Laboratory Director

Surgical Pathology Report **Preliminary Report
Name: Vargas, Danilo
Physician: Krieger, Mark M.D.

Diagnosis:
A. Skeletal muscle, left thigh, biopsy:
Consistent with mitochondrial myopathy
See comment

Ignacio Gonzalez,MD

Clinical History:
3 year old male with hx of mitochondria disease, unknown spinal cord myelopathy

Preoperative diagnosis:
Left muscle biopsy

Procedure: Left Thigh muscle biopsy

Speciment submitted: Muscle, lt thigh

Gross Description:
The specimen is received unfixed in the Operating Room, labeled with the patient’s name, medical record number and "Muscle biopsy, left thigh." It consists of an irregular fragment of tan muscle tissue which measures 1.2 x 0.8 x 0.6 cm in greatest dimensions. The specimen is entirely submitted as follows: A1 – glutaraldehyde fixed tissue, A2 – frozen tissue, saved.
RMA

Microscopic:
A. P&E [might be B&E; hard to read.sjm] stained sections reveal mild variation in muscle fiber size. The slightly smaller fibers are scattered without grouping. The number of internally located nuclei is not increased. There are few splitting fibers. Muscle fiber necrosis or degeneration are not present. There are no sarcoplasmic defects or inclusions. There is mild perimysial increase in collagen contents. The endomysial connective tissue and vascular structures are not remarkable. Inflammation not present.

Special Stains

Findings:
Modified trichrome stain.- The sarcoplasmic mitochondrial contents is increased in scattered fibers. Typical "ragged-red fibers" are not present.

Oil Red O stain.-The sarcoplasmic contents of neutral lipid droplets is increased in a subpopulation of muscle fibers.

Interpretation:
Results support the diagnosis.
Ignacio Gonzalez,MD

Comment:
Mitochondrial enzyme determination, DNA deletions and point mutation analysis and ultrastructure are pending. An addendum will be issued when results become available.

(Footer of report)
Timothy J. Triche, M.D.,Ph.D.
Pathologist-In-Chief and Chairman
Department of Pathology and Laboratory Medicine
4650 Sunset Blvd
Los Angeles, CA 90027
213-669-2426
CHILDREN’S HOSPITAL LOS ANGELES

Just FYI.In reviewing Danilo’s medical records, I see some inconsistencies.

1.Dr. Niparko wrote a long report on 2/28/2003 which states "Movements are mostly ataxic, but he also demonstrates a great deal of chorea, sometimes suspicious MYOCLONUS."[Capitalization mine]

In my last lengthy conversation with Niparko back in October regarding the possibility of OMS, she rather strenuously asserted that Danilo did NOT have myoclonus and didn’t want to refer the case to Dr.Wendy Mitchell, the OMS expert at Children’s Hospital.

(Incidentally, one website defines chorea as "an irregular, rapid, uncontrolled, involuntary, excessive movement that seems to move randomly from one part of the body to another")

2. Niparko told us that the early report on Danilo’s muscle biopsy showed that he had "ragged red fibers" and indicated mitochondrial myopathy.

However, according to the paper copy we obtained, Dr. Ignacio Gonzales’ July 22, 2003 preliminary report of Danilo’s muscle biopsy says "Typical ‘ragged-red fibers’ are NOT present." [Capitalization mine] Despite this, Gonzalez said the initial testing supported the mitochondrial disease diagnosis.

Notes to Oge & self

A.Demand copies of all documentation on Danilo’s case as it’s created going forward.

B.Recalibrate Bullshit Detectors.

In case anyone’s interested, this week I intend to post the text from Gonzales’ 7-22-03 preliminary report, some of the text from Athena Diagnostics report on the muscle biopsy from 7-23-03, and Georgetown University Medical Center’s report from 8-22-03.

Upcoming Appointments:
Dr. Niparko - Jan 9th
Dr. Pranzatelli - Jan. 21st in Springfield, IL
Jan 30 - ophthalmology appt
Feb. 5th - Dr. Mitchell at CHLA

Over the break, we got all the medical records. Getting them from Kaiser was not difficult, but I had to go in and talk real nice and friendly to the records people. Actually, they were very nice ... but I don't understand why it takes so long for doctors to get them. Maybe because they don't have to pay for them? Kaiser of course is all about money, I have decided...